Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use

ABSTRACT

Glucagon receptor antagonist compounds are disclosed. The compounds are useful for treating type 2 diabetes and related conditions. Pharmaceutical compositions and methods of treatment are also included.

BACKGROUND OF THE INVENTION

The present invention relates to glucagon receptor antagonist compounds,compositions containing such compounds and various methods of treatmentrelating to type 2 diabetes mellitus and related conditions.

Diabetes refers to a disease process derived from multiple causativefactors and is characterized by elevated levels of plasma glucose(hyperglycemia) in the fasting state or following glucose administrationduring an oral glucose tolerance test. Frank diabetes mellitus (e.g., ablood glucose level >126 mg/dL in a fasting state) is associated withincreased and premature cardiovascular morbidity and mortality, and isrelated directly and indirectly to various metabolic conditions,including alterations of lipid, lipoprotein and apolipoproteinmetabolism.

Patients with non-insulin dependent diabetes mellitus (type 2 diabetesmellitus), approximately 95% of patients with diabetes mellitus,frequently display elevated levels of serum lipids, such as cholesteroland triglycerides, and have poor blood-lipid profiles, with high levelsof LDLcholesterol and low levels of HDL-cholesterol. Those sufferingfrom Type 2 diabetes mellitus are thus at an increased risk ofdeveloping macrovascular and microvascular complications, includingcoronary heart disease, stroke, peripheral vascular disease,hypertension (for example, blood pressure >130/80 mmHg in a restingstate), nephropathy, neuropathy and retinopathy.

Patients having type 2 diabetes mellitus characteristically exhibitelevated plasma insulin levels compared with nondiabetic patients; thesepatients have developed a resistance to insulin stimulation of glucoseand lipid metabolism in the main insulin-sensitive tissues (muscle,liver and adipose tissues). Thus, Type 2 diabetes, at least early in thenatural progression of the disease is characterized primarily by insulinresistance rather than by a decrease in insulin production, resulting ininsufficient uptake, oxidation and storage of glucose in muscle,inadequate repression of lipolysis in adipose tissue, and excess glucoseproduction and secretion by the liver. The net effect of decreasedsensitivity to insulin is high levels of insulin circulating in theblood without appropriate reduction in plasma glucose (hyperglycemia).Hyperinsulinemia is a risk factor for developing hypertension and mayalso contribute to vascular disease.

Glucagon serves as the major regulatory hormone attenuating the effectof insulin in its inhibition of liver gluconeogenesis and is normallysecreted by alpha cells in pancreatic islets in response to fallingblood glucose levels. The hormone binds to specific receptors in livercells that trigger glycogenolysis and an increase in gluconeogenesisthrough cAMP-mediated events. These responses generate glucose (e.g.hepatic glucose production) to help maintain euglyeemia by preventingblood glucose levels from falling significantly. In addition to elevatedlevels of circulating insulin, type 2 diabetics have elevated levels ofplasma glucagon and increased rates of hepatic glucose production.Antagonists of the glucagon receptor are useful in improving insulinresponsiveness in the liver, decreasing the rate of gluconeogenesis andglycogenolysis, and lowering the rate of hepatic glucose outputresulting in a decrease in the levels of plasma glucose.

SUMMARY OF THE INVENTION

The present invention relates to a compound represented by formula I:

or a pharmaceutically acceptable salt or solvate thereof wherein:

each R¹ represents H or is selected from the group consisting of halo,CN, OH, NO₂, CO₂R^(a), NR^(a)R^(b), S(O)_(p)R^(a), C₁₋₁₀alkyl,C₂₋₁₀alkenyl or C₁₋₁₀alkoxy, the alkyl and alkenyl portions ofC₁₋₁₀alkyl, C₂₋₁₀alkenyl and C₁₋₁₀alkoxy being optionally substitutedwith 1-5 halo atoms up to perhalo; and further optionally substitutedwith 1 group selected from OH, oxo and C₁₋₆alkox_(Y);

p represents 0, 1 or 2;

each R^(a) and R^(b) independently represents H or C₁₋₄alkyl optionallysubstituted with 1-5 halo atoms up to perhalo; and further optionallysubstituted with 1 group selected from OH, oxo and C₁₋₆alkoxy;

R² represents C₁₋₆alkyl or C₂₋₆alkenyl, each optionally substituted with1-5 halo atoms up to perhalo, and further optionally substituted with 1group selected from OH, oxo and C₁₋₆alkoxy;

-   -   each R³ represents H or is selected from the group consisting of        halo; CN; OH; NO₂; CO₂R^(a); NR^(a)R^(b); S(O)_(p)R^(a); a        5-membered heteroaryl ring containing 1-3 nitrogen atoms, 0-1        oxygen or sulfur atom, and optionally substituted with 1-2        C₁₋₄alkyl groups; C₁₋₁₀alkyl; C₂₋₁₀ alkenyl and C₁₋₁₀alkoxy, the        alkyl and alkenyl portions of C₁₋₁₀alkyl, C₂₋₁₀alkenyl and        C₁₋₁₀alkoxy being optionally substituted with 1-5 halo atoms up        to perhalo; and further optionally substituted with 1 group        selected from OH, oxo, NR^(a)R^(b) and C₁₋₆alkoxy;

each R⁴ independently represents H or is selected from the groupconsisting of halo, OH, C₁₋₄alkyl, OC₁₋₄alkyl, haloC₁₋₄alkyl andhaloOC₁₋₄alkyl;

m represents 0, 1 or 2; such that when m represents 0 or 1, Z representstetrazolyl; and when m represents 2, Z represents a member selected fromthe group consisting of CO₂H, SO₃H and C(O)NH₂.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl and the like, means carbon chains which may be linear,branched, or cyclic, or combinations thereof, containing the indicatednumber of carbon atoms. If no number is specified, 1-10 carbon atoms areintended for linear or branched alkyl groups. Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl,pentyl, hexyl, heptyl, octyl, nonyl and the like. Cycloalkyl is a subsetof alkyl; if no number of atoms is specified, 3-10 carbon atoms areintended, forming 1-3 carbocyclic rings that are fused. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, decahydronaphthyl and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like. Cycloalkenyl is a subset of alkenyl. If no number isspecified, 4-8 carbon atoms are included. Examples includecyclopentenyl, cyclohexenyl and the like.

“Aryl” (Ar) means mono- and bicyclic aromatic rings containing 6-12carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and thelike. “Aryl” also includes monocyclic rings fused to an aryl group.Examples include tetrahydronaphthyl, indanyl and the like.

“Heteroaryl” (HAR) means a mono- or bicyclic aromatic ring or ringsystem containing at least one heteroatom selected from 0, S and N, witheach ring containing 5 to 6 atoms. Examples include pyrrolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl,thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl,triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl and the like.Heteroaryl also includes aromatic heterocyclic groups fused toheterocycles that are non-aromatic or partially aromatic, and aromaticheterocyclic groups fused to cycloalkyl rings. Heteroaryl also includessuch groups in charged form, e.g., pyridinium.

“Halogen” (Halo) includes fluorine, chlorine, bromine and iodine.Haloalkyl and haloalkoxy refer to halogenated alkyl and alkoxy groupshaving the indicated number of carbon atoms, substituted with one tofive halo atoms, up to perhalo, and preferably one to three halo atomsselected from fluoro and chloro. Thus, for example, haloC₁₋₆alkyl refersto a C₁₋₆alkyl group substituted with halo atoms, up to perhalo.

Numbering around the benzothiophene is conventional, as shown below:

It is also noted that while structures I, I-1 and I-2 depict the R³groups on the benzene ring of the benzothiophene moiety, the R³ groupscan be attached at any available point on the thiophene portion as well.

One aspect of the invention relates to a compound represented by formulaI:

or a pharmaceutically acceptable salt or solvate thereof wherein:

each R¹ represents H or is selected from the group consisting of halo,CN, OH, NO₂, CO₂R^(a), NR^(a)R^(b), S(O)_(p)R^(a), C₁₋₁₀alkyl,C₂₋₁₀alkenyl or C₁₋₁₀alkoxy, the alkyl and alkenyl portions ofC₁₋₁₀alkyl, C₂₋₁₀alkenyl and C₁₋₁₀alkoxy being optionally substitutedwith 1-5 halo atoms up to perhalo; and further optionally substitutedwith 1 group selected from OH, oxo and C₁₋₆aikoxY;

p represents 0, 1 or 2;

each R^(a) and R^(b) independently represents H or C₁₋₄alkyl optionallysubstituted with 1-5 halo atoms up to perhalo; and further optionallysubstituted with 1 group selected from OH, oxo and C₁₋₆alkoxy ;

R² represents C₁₋₆alkyl or C₂₋₆alkenyl, each optionally substituted with1-5 halo atoms up to perhalo, and further optionally substituted with 1group selected from OH, oxo and C₁₋₆alkoxy ;

each R³ represents H or is selected from the group consisting of halo;CN; OH; NO₂; CO₂R^(a); NR^(a)R^(b); S(O)_(p)R^(a); a 5-memberedheteroaryl ring containing 1-3 nitrogen atoms, 0-1 oxygen or sulfuratom, and optionally substituted with 1-2 C₁₋₄alkyl groups; C₁₋₁₀alkyl;C₂₋₁₀alkenyl and Cmoalkoxy, the alkyl and alkenyl portions ofC₁₋₁₀alkyl, C₂₋₁₀alkenyl and C₁₋₁₀ alkoxy being optionally substitutedwith 1-5 halo atoms up to perhalo; and further optionally substitutedwith 1 group selected from OH, oxo, NR^(a)R^(b) and C₁₋₆alkoxy;

each R⁴ independently represents H or is selected from the groupconsisting of halo, OH, C₁₋₄alkyl, OC₁₋₄alkyl, haloC₁₋₄alkyl andhaloOC₁₋₄alkyl;

m represents 0, 1 or 2; such that when m represents 0 or 1, Z representstetrazolyl; and when m represents 2, Z represents a member selected fromthe group consisting of CO₂H, SO₃H and C(O)NH₂.

An aspect of the invention that is of interest relates to a compound offormula I-1:

or a pharmaceutically acceptable salt or solvate thereof . The variablesare as defined with respect to formula I.

Another aspect of the invention that is of interest relates to acompound of formula I-2:

or a pharmaceutically acceptable salt or solvate thereof. The variablesare as defined with respect to formula I.

Another aspect of the invention that is of interest relates to compoundsin accordance with formula I or a pharmaceutically acceptable salt orsolvate thereof wherein each R¹ represents H or is selected from thegroup consisting of halo, CN, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl andhaloC₁₋₆alkoxy.

In particular, another aspect of the invention that is of interestrelates to compounds in accordance with formula I or a pharmaceuticallyacceptable salt or solvate thereof wherein each R¹ represents H or isselected from the group consisting of: halo selected from fluoro andchloro; CN; CH₃; OCH₃; CF₃ and OCF₃.

Another aspect of the invention that is of interest relates to compoundsin accordance with formula I or a pharmaceutically acceptable salt orsolvate thereof wherein R² represents a member selected from the groupconsisting of: C₁₋₆alkyl and C₃₋₄alkenyl, each optionally substitutedwith 1-3 halo atoms.

In particular, another aspect of the invention that is of interestrelates to compounds in accordance with formula I or a pharmaceuticallyacceptable salt or solvate thereof wherein R² represents C₂₋₅alkyloptionally substituted with 1-3 halo atoms.

Even more particularly, another aspect of the invention that is ofinterest relates to compounds in accordance with formula I or apharmaceutically acceptable salt or solvate thereof wherein R² isselected from the group consisting of ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl and 3-methylbutyl, each optionallysubstituted with 1-3 halo atoms selected from fluoro and chloro.

Even more particularly, another aspect of the invention that is ofinterest relates to compounds in accordance with formula I or apharmaceutically acceptable salt or solvate thereof wherein R² isselected from the group consisting of ethyl, n-propyl, n-butyl,CH₂CH(CH₃)₂, CH₂CH₂CH(CH₃)₂ and CH₂CH₂CF₃.

Another aspect of the invention that is of interest relates to compoundsin accordance with formula I or a pharmaceutically acceptable salt orsolvate thereof wherein each

R³ represents H or is selected from the group consisting of halo, CN,OH, SCH₃, SO₂CH₃, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxyand a 5-membered heteroaryl ring containing 1-2 nitrogen atoms and 0-1oxygen atom, said ring being optionally substituted with 1-2 C₁₋₄alkylgroups.

More particularly, another aspect of the invention that is of interestrelates to compounds in accordance with formula I or a pharmaceuticallyacceptable salt or solvate thereof wherein each R³ represents H or isselected from the group consisting of halo which is selected from F, Cland Br, CN, OH, SCH₃, SO₂CH₃, C₁₋₂alkyl, C₁₋₂alkoxy, haloC₁₋₂alkyl andhaloC₁₋₂alkoxy wherein the halo portion of haloC₁₋₂alkyl andhaloC₁₋₂alkoxy is selected from F and Cl, and a 5-membered heteroarylring containing 1-2 nitrogen atoms and 0-1 oxygen atom, said ring beingoptionally substituted with 1-2 C₁₋₄alkyl groups.

Even more particularly, another aspect of the invention that is ofinterest relates to compounds in accordance with formula I or apharmaceutically acceptable salt or solvate thereof wherein each R³represents H, F, Cl, Br, CN, OH, CH₃, OCH₃, OCH₂CH₃, CHF₂, CF₃, SCH₃,SO₂CH₃, OCHF₂, OCF₃ and a 5-membered heteroaryl ring containing 1-2nitrogen atoms, 0-1 oxygen atom and being optionally substituted with 1C₁₋₂alkyl group.

Another aspect of the invention that is of interest relates to compoundsin accordance with formula I or a pharmaceutically acceptable salt orsolvate thereof wherein each R⁴ represents H, halo selected from F andCl, OH, C₁₋₂alkyl, C₁₋₂alkoxy, haloC₁₋₂alkyl and haloC₁₋₂alkoxy whereinthe halo portion of haloC₁₋₂alkyl and haloC₁₋₂alkoxy is selected from Fand Cl.

In particular, another aspect of the invention that is of interestrelates to compounds in accordance with formula I or a pharmaceuticallyacceptable salt or solvate thereof wherein each R⁴ represents H, F, Cl,OH, CH₃, OCH₃, CF₃, and OCF₃.

More particularly, another aspect of the invention that is of interestrelates to compounds in accordance with formula I or a pharmaceuticallyacceptable salt or solvate thereof wherein each R⁴ represents H, F, CH₃or OH.

Another aspect of the invention that is of interest relates to compoundsin accordance with formula I or a pharmaceutically acceptable salt orsolvate thereof wherein m represents 0 or 1 and Z represents tetrazolyl.

Another aspect of the invention that is of interest relates to compoundsin accordance with formula I or a pharmaceutically acceptable salt orsolvate thereof wherein m is 2 and Z represents CO₂H.

Another aspect of the invention that is of interest relates to compoundin accordance with formula 1 or a pharmaceutically acceptable salt orsolvate thereof wherein:

each R¹ represents H or is selected from the group consisting of halo,CN, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl and haloC₁₋₆alkoxy;

R² represents a member selected from the group consisting of: C₁₋₆alkyland C₃₋₄alkenyl, each optionally substituted with 1-3 halo atoms;

each R³ represents H or is selected from the group consisting of halo,CN, OH, SCH₃, SO₂CH₃, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl,haloC₁₋₆alkoxy and a 5-membered heteroaryl ring containing 1-2 nitrogenatoms and 0-1 oxygen atom, said ring being optionally substituted with1-2 C₁₋₄alkyl groups;

each R⁴ represents H, halo selected from F and Cl, OH, C₁₋₂alkyl,C₁₋₂alkoxy, haloC₁₋₂alkyl and haloC₁₋₂alkoxy wherein the halo portion ofhaloC₁₋₂alkyl and haloC₁₋₂alkoxy is selected from F and Cl;

m is 0 or 1 and Z is tetrazolyl, or m is 2 and Z represents CO₂H.

Examples of compounds that fall within the invention described hereinare in the tables and examples contained herein. Pharmaceuticallyacceptable salts and solvates of the compounds disclosed in the tablesare included as well.

Another aspect of the invention that is of interest relates to apharmaceutical composition comprising a compound as described above withrespect to formula I or a pharmaceutically acceptable salt or solvatethereof in combination with a pharmaceutically acceptable carrier.

Another aspect of the invention that is of interest relates to a methodof treating type 2 diabetes mellitus in a mammalian patient in need ofsuch treatment comprising administering to said patient a compound asdescribed above with respect to formula I or a pharmaceuticallyacceptable salt or solvate thereof in an amount that is effective totreat type 2 diabetes mellitus.

Another aspect of the invention that is of interest relates to a methodof delaying the onset of type 2 diabetes mellitus in a mammalian patientin need thereof, comprising administering to the patient a compound asdescribed above in accordance with formula I or a pharmaceuticallyacceptable salt or solvate thereof in an amount that is effective todelay the onset of type 2 diabetes mellitus.

Another aspect of the invention that is of interest relates to a methodof treating hyperglycemia, diabetes or insulin resistance in a mammalianpatient in need of such treatment which comprises administering to saidpatient a compound as described above in accordance with formula I or apharmaceutically acceptable salt or solvate thereof in an amount that iseffective to treat hyperglycemia, diabetes or insulin resistance.

Another aspect of the invention that is of interest relates to a methodof treating non-insulin dependent diabetes mellitus in a mammalianpatient in need of such treatment comprising administering to thepatient an anti-diabetic effective amount of a compound in accordancewith formula I or a pharmaceutically acceptable salt or solvate thereofas described above.

Another aspect of the invention that is of interest relates to a methodof treating obesity in a mammalian patient in need of such treatmentcomprising administering to said patient a compound in accordance withformula I as described above or a pharmaceutically acceptable salt orsolvate thereof in an amount that is effective to treat obesity.

Another aspect of the invention that is of interest relates to a methodof treating Syndrome X in a mammalian patient in need of such treatment,comprising administering to said patient a compound in accordance withformula I as described above or a pharmaceutically acceptable salt orsolvate thereof in an amount that is effective to treat Syndrome X.

Another aspect of the invention that is of interest relates to a methodof treating a lipid disorder selected from the group consisting ofdyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL and high LDL in a mammalian patient inneed of such treatment, comprising administering to said patient acompound as described above with respect to formula I or apharmaceutically acceptable salt or solvate thereof in an amount that iseffective to treat said lipid disorder.

Another aspect of the invention that is of interest relates to a methodof treating atherosclerosis in a mammalian patient in need of suchtreatment, comprising administering to said patient a compound inaccordance with formula I as described above or a pharmaceuticallyacceptable salt or solvate thereof in an amount effective to treatatherosclerosis.

Another aspect of the invention that is of interest relates to a methodof treating a condition selected from the group consisting of: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) Syndrome X, and other conditions and disorders whereinsulin resistance is a component, in a mammalian patient in need ofsuch treatment, comprising administering to the patient a compound inaccordance with formula I as described above or a pharmaceuticallyacceptable salt or solvate thereof in an amount that is effective totreat said condition.

Another aspect of the invention that is of interest relates to a methodof delaying the onset of a condition selected from the group consistingof (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance,(4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia,(8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) Syndrome X, and other conditions and disorders whereinsulin resistance is a component in a mammalian patient in need of suchtreatment, comprising administering to the patient a compound inaccordance with formula I as described above or a pharmaceuticallyacceptable salt or solvate thereof in an amount that is effective todelay the onset of said condition.

Another aspect of the invention that is of interest relates to a methodof reducing the risk of developing a condition selected from the groupconsisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulinresistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7)hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10)low HDL levels, (11) high LDL levels, (12) atherosclerosis and itssequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominalobesity, (16) neurodegenerative disease, (17) retinopathy, (18)nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions anddisorders where insulin resistance is a component in a mammalian patientin need of such treatment, comprising administering to the patient acompound of foimula I as described above or a pharmaceuticallyacceptable salt or solvate thereof in an amount that is effective toreduce the risk of developing said condition.

Another aspect of the invention that is of interest relates to a methodof treating a condition selected from the group consisting of:

(1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance,(4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia,(8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (1.3)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) Syndrome X, and other conditions and disorders whereinsulin resistance is a component, in a mammalian patient in need ofsuch treatment,

comprising administering to the patient effective amounts of a compoundof formula I as described above, or a pharmaceutically acceptable saltor solvate thereof, and a another compound that is selected from thelist provided below.

(1) growth hormone secretagogues, growth hon none secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB₁ receptorantagonists or inverse agonists, such as rirnonaba.nt (SanofiSynthelabo), AMT-251, and SR-14778 and SR 141716A (Sandi Synthelabo),SLY-319 (Solvay), BAY 65-2520 (Bayer), and those disclosed in U.S. Pat.Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,W098/43636, W098/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, W002/076949, WO 03/007887, WO04/048317, and WO 05/000809; and EPO Application No. EP-658546,EP-656354, EP-576357; (4) anti-obesity serotonergic agents, such asfenfluramine, dexfenfluramine, phentemiine, and sibutramine;(5)133-adrenoreceptor agonists, such as AD9677/TAK677(Dainippon!Takeda), CL-316,243, SB 418790, BRL-37344, L-796568,BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR59119A, and such as those disclosed in U.S. Patent Application Nos.5,705,515, and U.S. Pat. No. 5,451,677 and PCT Patent PublicationsWO94/18161, WO95/29159, WO97/46556, WO98/04526 and W098/32753, WO01/74782, and WO 02/32897; (6) pancreatic lipase inhibitors, such asorlistat (Xenical®), cetilistat, Triton WR1339, RHC80267, lipstatin,tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate, andthose disclosed in PCT Application No. WO 01/77094; (7) neuropeptide Y1antagonists, such as B1BP3226, J-115814, BIBO 3304, LY-357897,CP-671906, GI-264879A, and those disclosed in U.S. Pat. No. 6,001,836,and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO 99/51600,WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8) neuropeptideY5 antagonists, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X,FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A,LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, and thosedisclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354; 6,166,038;6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332; 6,326,375;6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and 6,723,847,hereby incorporated by reference in their entirety; European Patent Nos.EP-01010691, and EP-01044970; and PCT International Patent PublicationNos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO98/24768; WO 98/25907; WO 98/25908; WO 98/27063, WO 98/47505; WO98/40356; WO 99/15516; WO 99127965; WO 00/64880, WO 00/68197, WO00/69849, WO 01/09120, WO 01/14376; WO 01/85714, WO 01/85730, WO01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO0248152, and WO 02/49648; WO 02/094825; WO 03/014083; WO 03/10191; WO03/092889; WO 04/002986; and WO 04/031175; (9) melanin-concentratinghormone (MCH) receptor antagonists, such as those disclosed in WO01/21577 and WO 01/21169; (10) melanin-concentrating hormone 1 receptor(MCH1R) antagonists, such as T-226296 (Takeda), and those disclosed inPCT Patent Application Nos. WO 01/82925, WO 01/87834, WO 02/051809, WO02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO02/083134, WO 02/094799, WO 03/004027, and Japanese Patent ApplicationNos. JP 13226269, and JP 2004-139909; (11) melanin-concentrating hormone2 receptor (MCH2R) agonist/antagonists; (12) orexin-1 receptorantagonists, such as SB-334867-A, and those disclosed in PCT PatentApplication Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838;(13) serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline, and those disclosed in U.S. Patent Application No.6,365,633, and PCT Patent Application Nos. WO 01/27060 and WO 01/162341;(14) melanocortin agonists, such as Melanotan II, CFI1R86036 (Chiron),ME-10142, and ME-10145 (Melacure), CH1R86036 (Chiron); PT-141, and PT-14(Palatin); (15) other MC4R (melanocortin 4 receptor) agonists, such asthose disclosed in: U.S. Pat. Nos. 6,410,548; 6,294,534; 6,350,760;6,458,790; 6,472,398; 6,376,509; and 6,818,658; US Patent PublicationNo. US2002/0137664; US2003/0236262; US2004/009751; US2004/0092501; andPCT Application Nos. WO 99/64002; WO 00/74679; WO 01/70708; WO 01/70337;WO 01/74844; WO 01/91752; WO 01/991752; WO 02/15909; WO 02/059095; WO02/059107; WO 02/059108; WO 02/059117; WO 02/067869; WO 02/068387; WO02/068388; WO 02/067869; WO 02/11715; WO 02/12166; WO 02/12178; WO03/007949; WO 03/009847; WO 04/024720; WO 04/078716; WO 04/078717; WO04/087159; WO 04/089307; and WO 05/009950; (16) 5HT-2 agonists; (17)5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215,WAY161503, R-1065, and those disclosed in U.S. Pat. No. 3,914,250, andPCT Application Nos, WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548,WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; (18) galaninantagonists; (19) CCK agonists; (20) CCK-1 agonists (cholecystokinin -A)agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 andSR146131, and those discribed in U.S. Pat. No. 5,739,106; (21) GLP-1agonists; (22) corticotropin-releasing hormone agonists; (23) histaminereceptor-3 (H3) modulators; (24) histamine receptor-3 (H3)antagonists/inverse agonists, such as hioperamide,3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit,iodophenpropit, imoproxifan, GT2394 (Gliatech), and those described anddisclosed in PCT Application No. WO 02/15905, andO-[3-(1H-imidazol-4-yl)propanol]-carbamates (Kiec-Kononowicz, K. et al.,Pharmazie, 55:349-55 (2000)), piperidine-containing histamineH3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32(2001), benzophenone derivatives and related compounds (Sasse, A. etal., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)),and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)); (25) β-hydroxy steroid dehydrogenase-1 inhibitors (β-HSD-1);(26) PD (phosphodiesterase) inhibitors, such as theophylline,pentoxifylline, zaprinast, amrinone, milrinone, cilostamide, rolipram,and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors; (28) NE(norepinephrine) transport inhibitors, such as GW 320659, despiramine,talsupram, and nomifensine; (29) ghrelin receptor antagonists, such asthose disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250;(30) leptin, including recombinant human leptin (PEG-OB, Hoffman LaRoche) and recombinant methionyl human leptin (Amgen); (31) leptinderivatives, such as those disclosed in U.S. Pat. Nos. 5,552,524,5,552,523, 5,552,522, 5,521,283, and PCT International Publication Nos.WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO96/23518, WO 96/23519, and WO 96/23520; (32) other BRS3 (bombesinreceptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron), and those disclosed in PCTApplication Nos. WO 94/09134, WO 98/22128, and WO 99/43813; (35)monoamine reuptake inhibitors, such as sibutrarnine, and those disclosedin U.S. Pat. Nos. 4,746,680, 4,806,570, and 5,436,272, U.S. PatentPublication No. 2002/0006964 and PCT Application Nos. WO 01/27068, andWO 01/62341; (36) UCP-1 (uncoupling protein-1), 2, or 3 activators, suchas phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid, and those disclosed in PCT PatentApplication No. WO 99/00123; (37) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS), and those disclosed in PCT Application No. WO02/15845, and Japanese Patent Application No. JP 2000256190; (38) FAS(fatty acid synthase) inhibitors, such as Cerulenin and C75; (39) DGAT1(diacylglycerol acyltransferase 1) inhibitors; (40) DGAT2(diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoAcarboxylase-2) inhibitors; (42) glucocorticoid antagonists; (43)acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M.et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV(DP-IV) inhibitors, such as isoleucine thiazolidide, valine pyrrolidide,NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011,P9310/K364, VIP 0177, SDZ 274-444 and sitagliptin; and the compoundsdisclosed in US Patent No. U.S. Pat. No. 6,699,871, which isincorporated herein by reference; and International Patent ApplicationNos. WO 03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO02/062764; WO 03/000250; WO 03/002530; WO 03/002531; WO 03/002553; WO03/002593; WO 03/000180; and WO 03/000181; (45) dicarboxylatetransporter inhibitors; (46) glucose transporter inhibitors; (47)phosphate transporter inhibitors; (48) Metformin (Glucophage®); (49)Topiramate (Topimax®); (50) peptide YY, PYY 3-36, peptide YY analogs,derivatives, and fragments such as BTM-43073D, BTM-43004C (Olitvak, D.A. et al., Dig. Dis. Sci. 44(3):643-48 (1999)), and those disclosed inU.S. Pat. No. 5,026,685, U.S. Pat. No. 5,604,203, U.S. Pat. No.5,574,010, U.S. Pat. No. 5, 696,093, U.S. Pat. No. 5,936,092, U.S. Pat.No. 6,046, 162, U.S. Pat. No. 6,046,167, U.S. Pat. No. 6,093,692, U.S.Pat. No. 6,225,445, U.S. Pat. No. 5,604,203, U.S. Pat. No. 4,002,531,U.S. Pat. No. 4, 179,337, U.S. Pat. No. 5,122,614, U.S. Pat. NO.5,349,052, U.S. Pat. No. 5,552,520, U.S. Pat. No. 6, 127,355, WO95/06058, WO 98/32466, WO 03/026591, WO 03/057235, WO 03/027637, and WO2004/066966; (51) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36,N acetyl [Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP) as described in Batterham etal., J. Clin. Endocrinol. Metab. 88:3989-3992 (2003), and other Y4agonists such as 1229U91; (53) cyclooxygenase-2 inhibitors such asetoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070,tiracoxib or JTE522, ABT963, CS502 and GW406381, and pharmaceuticallyacceptable salts thereof; (54) Neuropeptide Y1 (NPY1) antagonists suchas B1BP3226, J-I 15814, BIBO 3304, LY-357897, CP-671906, GI-264879A andthose disclosed in U.S. Pat. No. 6,001,836; and PCT Application Nos. WO96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO01/85173, and WO 01/89528; (55) Opioid antagonists such as nalmefene(Revex®), 3-methoxynaltrexone, naloxone, naltrexone, and those disclosedin: PCT Application No. WO 00/21509; (57) 11β HSD-1 (11-beta hydroxysteroid dehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, andthose disclosed in WO 01/90091, WO 01/90090, WO 01/90092, and U.S. Pat.No. 6,730,690 and US Publication No. US 2004-0133011, which areincorporated by reference herein in their entirety; (56) aminorex; (57)amphechloral; (58) amphetamine; (59) benzphetamine; (60)chlorphentermine; (61) clobenzorex; (62) cloforex; (63) clominorex; (64)clortermine; (65) cyclexedrine; (66) dextroamphetamine; (67)diphemethoxidine, (68) N-ethylamphetamine; (69) fenbutrazate; (70)fenisorex; (71) fenproporex; (72) fludorex; (73) fluminorex; (74)furfurylmethylamphetamine; (75) levamfetamine; (76) levophacetoperane;(77) mefenorex; (78) metamfepramone; (79) methamphetamine; (80)norpseudoephedrine; (81) pentorex; (82) phendimetrazine; (83)phenmetrazine; (84) picilorex; (85) phytopharm 57; (86) zonisamide, (87)neuromedin U and analogs or derivatives thereof, (88) oxyntomodulin andanalogs or derivatives thereof, (89) Neurokinin-1 receptor antagonists(NK-1 antagonists) such as the compounds disclosed in: U.S. Pat. Nos.5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270,5,494,926, 5,496,833, and 5,637,699; (90) Qnexa; (91) smoking cessationagents, such as nicotine agonists, partial nicotine agonists, such asvarenicline, monoamine oxidase inhibitors (MAOIs), antidepressants suchas bupropion, doxepine, and nortriptyline; and anxiolytic agents such asbuspirone or clonidine.

Specific compounds of use in combination with a compound of the presentinvention include: simvastatin, mevastatin, ezetimibe, atorvastatin,sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate,naltrexone, bupriopion, phentermine, and losartan, losartan withhydrochlorothiazide. Specific CB1 antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO03/077847, including:N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,and pharmaceutically acceptable salts thereof; as well as those inWO05/000809, which includes the following:3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile,1-{1-[1-(4-ehlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol.3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((4-chlorophenyl){3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenypmethyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,and5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile,and pharamecueitcally acceptable salts thereof; as well as:3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-cyanophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-(3-{(1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1-methyl-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl-2H-tetrazole,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,5-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,3,4-oxadiazol-2(3H)-one,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluro-2-methylpropyl]-5-fluorobenzonitrile,3-(((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadidazol-2-yl)phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,3-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyI)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile, and pharmaceuticallyacceptable salts thereof.

Specific NPY5 antagonists of use in combination with a compound of thepresent invention include:3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofiiran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1′(3H),1′-cyclohexane]-4′-carboxamide,and pharmaceutically acceptable salts and esters thereof.

Specific ACC-1/2 inhibitors of use in combination with a compound of thepresent invention include:1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;(5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methylpivalate;5-{1′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinicacid;1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and pharmaceutically acceptable salts and esters thereof. Specific MCHIRantagonist compounds of use in combination with a compound of thepersent invention include:1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one,4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl)methoxy]pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,and4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(1H)-one,or a pharmaceutically acceptable salt thereof.

Specific DP-IV inhibitors of use in combination with a compound of thepresent invention are selected from7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine.In particular, the compound of formula I is favorably combined with7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine,and pharmaceutically acceptable salts thereof.

Specific 113 (histamine H3) antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO05/077905,including:3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazoline,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazoline,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyppropoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,and pharmaceutically acceptable salts thereof.

Specific CCK1R agonists of use in combination with a compound of thepresent invention include:3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid;3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; 3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid;3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; and3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl1-1-piperazinyl)-1-naphthoicacid; and pharmaceutically acceptable salts thereof.

Specific MC4R agonists of use in combination with a compound of thepresent invention include: 1)(5S)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];2)(5R)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];3)2-(1′-{[3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl)-2-methylpropanenitrile;4)1′-{[(3,5,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];5)N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1′H,5H-spiro[furo-[3,4-b]pyridine-7,4′-piperidin]-1′-yl}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-amine;6)2-[3-chloro-1′-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl}-2-methyl-5H-spiro[furo[3,4-bpyridine-7,4′-piperidin]-5-yl]-2-methyl-propane-nitrile; andpharmaceutically acceptable salts thereof. Still further, neurokinin-1(NK-1) receptor antagonists may be favorably employed in combinationwith a compound of the present invention. NK-1 receptor antagonists ofuse in the present invention are fully described in the art. Specificneurokinin-1 receptor antagonists of use in the present inventioninclude:(±)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;aperpitant; C.117493; GW597599; GW679769; R673; RO67319; R1124; R1204;SSR146977; SSR240600; T-2328; and T2763.; or a pharmaceuticallyacceptable salts thereof. Examples of other anti-obesity agents that canbe employed in combination with a compound of formula I are disclosed in“Patent focus on new anti-obesity agents,” Exp. Opin. Ther. Patents, 10:819-831 (2000); “Novel anti-obesity drugs,” Exp. Opin. Invest. Drugs, 9:1317-1326 (2000); and “Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity, Exp. Opin.Ther. Patents, 11: 1677-1692 (2001). The role of neuropeptide Y inobesity is discussed in Exp. Opin. Invest. Drugs, 9: 1327-1346 (2000).Cannabinoid receptor ligands are discussed in Exp. Opin. Invest. Drugs,9: 1553-1571 (2000).

Another aspect of the invention that is of interest relates to a methodof treating a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalianpatient in need of such treatment, comprising administering to thepatient therapeutically effective amounts of a compound of formula I asdescribed above and an HMG-CoA reductase inhibitor.

More particularly, another aspect of the invention that is of interestrelates to a method of treating a condition selected from the groupconsisting of hypercholesterolemia, atherosclerosis, low HDL levels,high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia,in a mammalian patient in need of such treatment, comprisingadministering to the patient therapeutically effective amounts of acompound of formula I as described above and an HMG-CoA reductaseinhibitor wherein the HMG-CoA reductase inhibitor is a statin. Even moreparticularly, another aspect of the invention that is of interestrelates to a method of treating a condition selected from the groupconsisting of hypercholesterolemia, atherosclerosis, low HDL levels,high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia,in a mammalian patient in need of such treatment, comprisingadministering to the patient therapeutically effective amounts of acompound of formula I as described above and an HMG-CoA reductaseinhibitor, wherein the HMG CoA reductase inhibitor is a statin selectedfrom the group consisting of lovastatin, simvastatin, pravastatin,fluvastatin, atorvastatin, itavastatin, rosuvastatin and rivastatin.

Another aspect of the invention that is of interest relates to a methodof reducing the risk of developing a condition selected from the groupconsisting of hypercholesterolemia, atherosclerosis, low HDL levels,high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia,and the sequelae of such conditions, delaying the onset or reducing therisk of developing said condition, comprising administering to amammalian patient in need of such treatment therapeutically effectiveamounts of a compound of formula I as described above and an HMG-CoAreductase inhibitor.

More particularly, another aspect of the invention that is of interestrelates to a method for delaying the onset of, or reducing the risk ofdeveloping atherosclerosis in a human patient in need of such treatmentcomprising administering to said patient effective amounts of a compoundof formula I as described above and an HMG-CoA reductase inhibitorwherein the HMG-CoA reductase inhibitor is a statin, and even moreparticularly, a statin selected from the group consisting of:lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,itavastatin, rosuvastatin and rivastatin.

Yet even more particularly, another aspect of the invention that is ofinterest relates to a method for delaying the onset or reducing the riskof developing atherosclerosis in a human patient in need of suchtreatment comprising administering to said patient effective amounts ofa compound of foiinula I as described above and an HMG-CoA reductaseinhibitor wherein the HMG-CoA reductase inhibitor is simvastatin,atorvastatin or rosuvastatin.

Another aspect of the invention that is of interest relates to a methodfor delaying the onset or reducing the risk of developingatherosclerosis in a human patient in need of such treatment comprisingadministering to said patient effective amounts of a compound of formulaas described above and a cholesterol absorption inhibitor. Moreparticularly, another aspect of the invention that is of interestrelates to a method for delaying the onset or reducing the risk ofdeveloping atherosclerosis in a human patient in need of such treatmentcomprising administering to said patient effective amounts of a compoundof formula I as described above and a cholesterol absorption inhibitorwherein the cholesterol absorption inhibitor is ezetimibe.

Another aspect of the invention that is of interest relates to a methodfor delaying the onset or reducing the risk of developing the otherdiseases and conditions mentioned above, in a mammalian patient in needof such treatment comprising administering to said patient effectiveamounts of a compound of formula I as described above, and a cholesterolabsorption inhibitor.

More particularly, another aspect of the invention that is of interestrelates to a method for delaying the onset or reducing the risk ofdeveloping the other diseases and conditions mentioned above, in a humanpatient in need of such treatment comprising administering to saidpatient effective amounts of a compound of formula I as described above,and a cholesterol absorption inhibitor, wherein the cholesterolabsorption inhibitor is ezetimibe.

Another aspect of the invention that is of interest relates to a methodof treating, delaying the onset, or preventing a condition selected fromthe group consisting of hypercholesterolemia, atherosclerosis, low HDLlevels, high LDL levels, hyperlipidemia, hypertriglyceridemia anddyslipidemia, in a mammalian patient in need of such treatment,comprising administering to the patient therapeutically effectiveamounts of a compound of formula I or a pharmaceutically acceptable saltor solvate thereof, and a CETP inhibiting. compound.

More particularly, an aspect of the invention that is of interestrelates to a method of treating, delaying the onset, or preventing acondition selected from the group consisting of hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,hypertriglyceridemia and dyslipidemia, in a mammalian patient in need ofsuch treatment, comprising administering to the patient therapeuticallyeffective amounts of a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof, and a CETP inhibiting compoundselected from torcetrapib and anacetrapib.

Another aspect of the invention that is of interest relates to apharmaceutical composition comprising (1) a compound of formula I asdescribed above; (2) a compound selected from the list provide above incombination with a pharmaceutically acceptable carrier.

One pharmaceutical composition that is of interest is comprised of acompound of formula I as described herein, or a pharmaceuticallyacceptable salt or solvate thereof, in combination with a DPP-IVinhibitor selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof in combinationwith a pharmaceutically acceptable carrier.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Many of the compounds of formula I contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent invention includes all such isomeric forms of the compounds, inpure form as well as in mixtures.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. Such an example maybe a ketone and its enol form known as keto-enol tautomers. Theindividual tautomers as well as mixtures thereof are encompassed withthe compounds of Formula I.

Salts and Solvates

Salts and solvates of compounds of formula I are included in the presentinvention. The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable substantially non-toxic basesor acids including inorganic or organic bases and inorganic or organicacids, as well as salts that can be converted into pharmaceuticallyacceptable salts. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium, and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, NN-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonie, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

Solvates as used herein refers to the compound of formula I or a saltthereof, in association with a solvent, such as water. Representativeexamples include hydrates, hemihydrates, trihydrates and the like.

References to the compounds of Formula I are intended to include thepharmaceutically acceptable salts and solvates.

In the compounds described herein, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the formulasdescribed herein. For example, different isotopic forms of hydrogen (H)include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within the formulas described herein canbe prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

This invention relates to a method of inhibiting the activity ofglucagon by antagonizing the glucagon receptor, thereby reducing therate of gluconeogenesis and glycogenolysis, and the concentration ofglucose in plasma.

The compounds of formula I can be used in the manufacture of amedicament for the prophylactic or therapeutic treatment of diseasestates in mammals associated with elevated levels of glucose, comprisedof combining the compound of formula I with the carrier materials toprovide the medicament.

Dose Ranges

The prophylactic or therapeutic dose of a compound of formula I will, ofcourse, vary with the nature or severity of the condition to be treated,the particular compound selected and its route of administration. Itwill also vary according to the age, weight and response of theindividual patient. In general, the daily dose range lies within therange of from about 0.001 mg to about 100 mg per kg body weight,preferably about 0.01 mg to about 50 mg per kg, and more preferably 0.1to 10 mg per kg, in single or divided doses. It may be necessary to usedosages outside of these limits in some cases. The terms “effectiveamount”, “anti-diabetic effective amount” and the other terms appearingthroughout the application addressing the amount of the compound to beused refer to the dosage ranges provided, taking into account anynecessary variation outside of these ranges, as deteimined by theskilled physician.

Representative dosages of compounds of formula I, as well as thepharmaceutically acceptable salts and solvates thereof, for adults rangefrom about 0.1 mg to about 1.0 g per day, preferably about 1 mg to about500 mg, in single or divided doses. Examples of suitable dosages include0.1mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 75 mg, 100 mg, 150mg, 200 mg, 250 mg, 500 mg, 1000 mg and similar such doses.

Representative dosages of compounds used in combination with thecompounds of formula I are known, or the determination thereof is withinthe level of skill in the art, taking into account the descriptionprovided herein.

When intravenous or oral administration is employed, a representativedosage range is from about 0.001 mg to about 100 mg (preferably from0.01 mg to about 10 mg) of a compound of Formula I per kg of body weightper day, and more preferably, about 0.1 mg to about 10 mg of a compoundof formula I per kg of body weight per day.

Phaimaceutical Compositions

As mentioned above, the pharmaceutical composition comprises a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereofand a pharmaceutically acceptable carrier. The term “composition”encompasses a product comprising the active and inert ingredient(s),(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, from thecombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions between ingredients.Preferably the composition is comprised of a compound of formula I in anamount that is effective to treat, prevent or delay the onset of type 2diabetes mellitus, in combination with the pharmaceutically acceptablecarrier.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Examples ofdosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols and the like, with oraltablets being preferred.

In preparing oral compositions, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like, in thecase of oral liquids, e.g., suspensions, elixirs and solutions; orcarriers such as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike in the case of oral solids, e.g., powders, capsules and tablets.Solid oral preparations are preferred. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit forms. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyacceptable pharmaceutical process. All such methods include the step ofcombining the active ingredient(s) with the carrier components. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient(s) with a liquid or finely divided solidcarrier component, and then, if necessary, manipulating the blend intothe desired product form. For example, a tablet may be prepared bycompression or molding. Compressed tablets may be prepared bycompressing free-flowing powder or granules, containing the active(s)optionally mixed with one or more excipients, e.g., binders, lubricants,diluents, surfactants and dispersants. Molded tablets may be made bymolding a mixture of the powdered compound moistened with an inertliquid. Desirably, each tablet may contain, for example, from about 0.1mg to about 1.0 g of the active ingredient and each cachet or capsulecontains from about 0.1 mg to about 500 mg of the active ingredient.

The following are examples of pharmaceutical dosage forms containing acompound of Formula I:

Injectable Suspension (im.) mg/mL Tablet Mg/tablet Compound of 10.0Compound of Formula 1 25.0 Formula 1 Methylcellulose 5.0Microcrystalline 415 Cellulose Tween 80 0.5 Povidone 14.0 Benzyl alcohol9.0 Pregelatinized Starch 4.0 Benzalkonium 1.0 Magnesium Stearate 2.5chloride Water for injection t.d. 1.0 mL Total (approx.) 460 mg

Capsule mg/cagsule Aerosol Per Canister Compound of 25.0 Compound ofFormula 1 250 mg Formula 1 Lactose 735 Lecithin, NF Liq. Conc. 1.2 mg MgStearate 1.5 Trichloromethane, NF 4.025 g Total (approx.) 761.5 mgDichlorodifluoro- 12.15 g methane, NF

Combination Therapy

As previously described, the compounds of Formula I may be used incombination with other drugs that are used in thetreatment/prevention/delaying the onset of type 2 diabetes mellitus, aswell as other diseases and conditions described herein, for whichcompounds of Formula I are useful. Other drugs may be administered, by aroute and in an amount commonly used, contemporaneously or sequentiallywith a compound of Formula I. When a compound of Formula I is usedcontemporaneously with one or more other drugs, a combinationpharmaceutical composition containing such other drugs in addition tothe compound of Formula I is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that alternativelycontain one or more other active ingredients, in addition to a compoundof Formula I. Examples of other active ingredients that may be combinedwith a compound of Formula I, either administered separately or in thesame pharmaceutical compositions, include, but are not limited to: (a)biguanides (e g., buformin, metformin, phenformin), (b) PPAR agonists(e.g., troglitazone, pioglitazone, rosiglitazone), (c) insulin, (d)somatostatin, (e) alpha-glucosidase inhibitors (e.g., voglibose,miglitol, acarbose), (f) DPP-IV inhibitors, such as sitagliptin,vildagliptin, saxagliptin, and the like, such as those disclosed in U.S.Pat. No. 6,699,871B1 granted on Mar. 2, 2004 (g) LXR modulators and (h)insulin secretagogues (e.g., acetohexamide, carbutamide, chlorpropamide,glibomuride, gliclazide, glimerpiride, glipizide, gliquidine,glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide,tolazamide, tolbutamide, tolcyclamide, nateglinide and repaglinide), andCBI inhibitors, such as rimonabant and those compounds disclosed inWO03/077847A2 published on Sep. 25, 2003 and in WO05/000809 A1 publishedon Jan. 6, 2005.

An aspect of the invention that is particular interest relates to apharmaceutical composition that is comprised of a compound of formula 1,or a pharmaceutically acceptable salt thereof, and a member selectedfrom the group consisting of: simvastatin, mevastatin, ezetimibe,atorvastatin, metformin, sibutramine, orlistat, Qnexa, topiramate,naltrexone, bupriopion, phentermine, losartan, hydrochlorothiazide,buformin, phenformin, troglitazone, pioglitazone, rosiglitazone,insulin, somatostatin, voglibose, miglitol, acarbose, sitagliptin,vildagliptin, saxagliptin, alogliptin, acetohexamide, carbutamide,chlorpropamide, glibomuride, gliclazide, glimerpiride, glipizide,gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide,phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide andrepaglinide, rimonabant and taranabant, in combination with apharmaceutically acceptable carrier.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied within wide limits and depends upon theeffective dose of each active ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the FormulaI is combined with a PPAR agonist the weight ratio of the compound ofthe Formula I to the PPAR agonist will generally range from about 1000:1to about 1:1000, preferably about 200:1 to about 1:200. Combinations ofa compound of the Formula I and other active ingredients will generallyalso be within the aforementioned range, but in each case, an effectivedose of each active ingredient should be used.

When used in combination with other agents, the dosages noted above forthe glucagon antagonist are provided along with the usual dose for theother medication. For example, when a DPP-IV inhibitor such as thosedisclosed in U.S. Pat. No. 6,699,871B1, is included, the DPP-IVinhibitor can be used in an amount ranging from about 1.0 mg to as highas about 1000mg, preferably about 2.5 mg to about 250 mg, and inparticular, about 50 mg or about 100 mg administered in single dailydoses or in divided doses as appropriate. Similarly, when the glucagonreceptor antagonist is used in combination with a CB1 antagonist/inverseagonist, the CB1 antagonist/inverse agonist can be used in an amountranging from as low as about 0.1 mg to as high as about 1000 mg, moreparticularly, in an amout ranging from about 1.0 mg to about 100 mg, andeven more particularly, in an amount from about 1.0 mg to about 10 mg,administered in single daily doses or in divided doses as appropriate.Examples of doses of CB1 antagonist/inverse agonist include ling, 2 mg,3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg and 20 mg.

Methods of Synthesis:

Compounds of the present invention can be prepared according to theSchemes provided below as well as the procedures provided in theExamples. The substituents are the same as in the above Formulas exceptwhere defined otherwise or otherwise apparent to the ordinary skilledartisan.

The novel compounds of the present invention can be readily synthesizedusing techniques known to those skilled in the art, such as thosedescribed, for example, in Advanced Organic Chemistry, March, 5^(th)Ed., John Wiley and Sons, New York, N.Y., 2001; Advanced OrganicChemistry, Carey and Sundberg, Vol. A and B, 3^(rd) Ed., Plenum Press,Inc., New York, N.Y., 1990; Protective groups in Organic Synthesis,Green and Wuts, 2^(nd) Ed., John Wiley and Sons, New York, N.Y., 1991;Comprehensive Organic Transformations, Larock, Val Publishers, Inc., NewYork, N.Y., 1988; Handbook of Heterocyclic Chemistry, Katritzky andPozharskii, 2^(nd) Ed., Pergamon, New York, N.Y., 2000 and referencescited therein. The starting materials for the present compounds may beprepared using standard synthetic transformations of chemical precursorsthat are readily available from commercial sources, including AldrichChemical Co. (Milwaukee, Wis.); Sigma Chemical Co. (St. Louis, Mo.);Lancaster Synthesis (Windham, N.H.); Ryan Scientific (Columbia, S.C.);Maybridge (Cornwall, UK); Matrix Scientific (Columbia, S. C.); Acros,(Pittsburgh, Pa.); BioBlocks, Inc. (San Diego, Calif.); and Trans WorldChemicals (Rockville, Md.).

The procedures described herein for synthesizing the compounds mayinclude one or more steps of protecting group manipulations and ofpurification, such as, re-crystallization, distillation, columnchromatography, flash chromatography, thin-layer chromatography (TLC),and high-pressure chromatography (HPLC). The products can becharacterized using various techniques well known in the chemical arts,including proton and carbon-13 nuclear magnetic resonance (¹H and ¹³CNMR), infrared and ultraviolet spectroscopy OR and UV), X-raycrystallography, elemental analysis and HPLC and mass spectrometry(HPLC-MS). Methods of protecting group manipulation, purification,structure identification and quantification are well known to oneskilled in the art of chemical synthesis.

Appropriate solvents are those which will at least partially dissolveone or all of the reactants and will not adversely interact with eitherthe reactants or the product. Suitable solvents are aromatichydrocarbons (e.g, toluene, xylenes), halogenated solvents (e.g,methylene chloride, chloroform, carbontetrachloride, chlorobenzenes),ethers (e.g, diethyl ether, diisopropylether, tert-butyl methyl ether,diglyme, tetrahydrofuran, dioxane, anisole), nitriles (e.g,acetonitrile, propionitrile), ketones (e.g, 2-butanone, dithyl ketone,Cert-butyl methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol,iso-propanol, n-butanol, t-butanol), N,N-dimethyl formamide (DMF),dimethylsulfoxide (DMSO) and water, Mixtures of two or more solvents canalso be used. Suitable bases are, generally, alkali metal hydroxides,alkaline earth metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide;alkali metal hydrides and alkaline earth metal hydrides such as lithiumhydride, sodium hydride, potassium hydride and calcium hydride; alkalimetal amides such as lithium amide, sodium amide and potassium amide;alkali metal carbonates and alkaline earth metal carbonates such aslithium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, and cesium hydrogen carbonate; alkali metal alkoxides andalkaline earth metal alkoxides such as sodium methoxide, sodiumethoxide, potassium tert-butoxide and magnesium ethoxide; alkali metalalkyls such as methyllithium, n-butyllithium, sec-butyllithium,t-bultyllithium, phenyllithium, alkyl magnaesium halides, organic basessuch as trimethylamine, triethylamine, triisopropylamine,N,N-diisopropylethyl amine, piperidine, N-methyl piperidine, morpholine,N-methyl morpholine, pyridine, collidines, lutidines, and4-dimethylaminopyridine; and bicyclic amines such as DBU and DABCO.

It is understood that the functional groups present in compoundsdescribed in the Schemes below can be further manipulated, whenappropriate, using the standard functional group transformationtechniques available to those skilled in the art, to provide desiredcompounds described in this invention.

Throughout the synthesis schemes, abbreviations are used with thefollowing meanings unless otherwise indicated:

AIBN = azobisisobutyronitrile aq = aqueous BINAP =2,2′-bis(diphenylphosphino)- Bn = benzyl 1,1′-binaphthalene BOC, Boc =t-butyloxycarbonyl BOP = benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate Bu = butyl, t-Bu =t-butyl BuLi, n-BuLi = n-butyllithium CBZ, Cbz = Benzyloxycarbonyl CDI =1,1′-carbonyldiimidazole (S)-DAIPEN = (S)-1,1-di(4-anisyl)-2- dba =dibenzylideneacetone = trans,trans- isopropyl-1,2-ethylenediamine =(S)-1,1- 1,5-diphenyl-1,4-pentadien-3-onebis(4-methoxyphenyl)-3-methylbutane- 1,2-diamine DCM = dichloromethane2,4-diClPh = 2,4-dichlorophenyl DIEA = diisopropylethylamine DMAP =4-Dimethylaminopyridine DMF = N,N-dimethylformamide DMS = dimethylsulfide DMSO = dimethyl sulfoxide dppf =1,1′-bis(diphenylphosphino)ferrocene EDC = 1-ethyl-3-(3- eq. =equivalent(s) dimethylaminopropyl)-carbodiimide Et = ethyl EtOAc = ethylacetate EtOH = ethanol g = gram(s) HOBT, HOBt = 1-hydroxybenzotriazoleHPLC = High pressure liquid chromatography IPA = isopropanol =2-propanol iPr = isopropyl = 2-propyl KHMDS = potassium KOtBu =potassium tert-butoxide bis(trimethylsilyl)amide LC/MS = liquidchromatography - mass LDA = lithium diisopropylamide spectrometry LHMDS= lithium M = molar bis(trimethylsilyl)amide mCPBA =3-chloroperoxybenzoic acid Me = methyl MeCN, CH₃CN = acetonitrile MeOH =methanol mg = milligram(s) mL = milliliter(s) mmol = millimole(s) N =normal NaOtBu = sodium tert-butoxide NBS = N-bromosuccinimide NCS =N-chlorosuccinimide n-Pr = n-propyl PCC = pyridinium chlorochromate Pd/C= palladium on activated carbon Ph = phenyl PyBOP = Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT, rt = roomtemperature TBAF = tetrabutylammonium fluoride Tf = triflate =trifluoromethanesulfonate TFA = Trifluoroacetic acid THF =tetrahydrofuran TMS = trimethylsilyl Tr = trityl = triphenylmethyl(S)-xyl-SEGPHOS = (S)-5,5′-Bis[di(3,5-xylyl)phosphino]-4,4′-bi-1,3-benzodioxole

Compounds of the present invention may be prepared according to themethodology outlined in the following general synthetic schemes.

Multiple embodiments of the present invention are summarized in Scheme 1which depicts the preparation of compounds Ia, Ib, and Ic from theacid 1. It is noted that the benzothiophene can be substituted with R³at any available point of attachment. Moreover, the benzothiophene canbe attached to the remainder of the molecule at position 2 or 3. Thecarboxylic acid intermediate I is coupled with substituted orunsubstituted beta alanine ester (either methyl, ethyl or t-butyl ester)using benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate (BOP) and a base, generallyN,N-diisopropylethylamine (DIEA), in a solvent such asN,N-dimethylformamide (DMF) or acetonitrile at ambient temperature toyield compound 2. Alternatively, the conversion of 1 to 2 may be carriedout with EDC, HOBt, and a base such as DIEA in similar solvents as thoseused with BOP and DIEA. Many additional peptide coupling conditions areknown and may also be used. Saponification of ester 2 (methyl, ethyl) togive compound Ia is achieved with a base such as aqueous lithiumhydroxide (LiOH) or aqueous sodium hydroxide in a polar solvent such astetrahydrofuran, methanol, ethanol or a mixture of similar solvents. Inaddition, compound 2, containing a t-butyl ester, can be converted tocompound Ia using acid such as acetic acid or trifluoroacetic acid(TFA). In additional embodiments of the invention, compounds Ib and Icmay be prepared directly from acid 1 by coupling with the appropriatelysubstituted amine using the peptide coupling methods described for thepreparation of amide 2.

Scheme 2 summarizes the preparation of acid intermediate 1 usingprocedures adapted from Organic Letters, Chung, et. al., 2008, 10,3037-3040. Coupling of aryl alkyl ketones 3 and aryl bromide 4 may beachieved under transition-metal mediated conditions such as thosedescribed in J. Am. Chem. Soc., Buchwald, S. L., et. al., 2000, 122,1360-1370. Ketone 5 may be prepared, for instance, by heating 3 and 4 inthe presence of a palladium source such as Pd₂(dba)₃, a ligand such asBINAP, a base such as NaOtBu, and a solvent such as THF. Reduction ofketone 5 to alcohol 6 can be accomplished with various achiralreductants, for instance NaBH₄. Alternatively, dynamic kineticresolution of ketone 5 can afford highly enantio- and diastereoenrichedalcohol 6 using catalysts such as those reviewed extensively in Angew.Chem., Int. Ed., Noyori, R., et. al., 2001, 40, 40-73. For instance,this reaction can be performed using a ruthenium catalyst such asRuCl₂[(S)-xyl-SEGPHOS][(S)-DAIPEN] and a base such as KOtBu in a solventsuch as 2-propanol under an atmosphere of hydrogen.

Deprotection of the t-butyl ester of alcohol 6 with an acid such asphosphoric acid in acetonitrile solvent gives the acid 7.

Acid 1 may then be accessed by treatment of 7 with a benzothiophene 8 indichloromethane solvent at ambient temperature or 60° C. followed by theaddition of a Bronsted acid such as trifluoroacetic acid (TFA) or aLewis acid such as boron trifluoride-diethyl etherate. A wide range ofsubstituents may be introduced at R¹, R², and R³ on acid 1 due to thefunctional group tolerance of the reactions employed in its preparationand the wide variety of starting benzothiophenes 8 and ketones 3 whichare either commercially available or readily prepared by methods knownto those skilled in the art.

While the R³ substituents are typically present in the starting materialbenzothiophene 8, it is also possible to alter the R³ substituents onadvanced intermediates as shown in Scheme 3. For instance, a bromidesubstituent may be further functionalized using a variety ofmetal-mediated cross-coupling reactions obvious to those skilled in theart. For instance, the bromide substituent of intermediate 2a may beconverted to nitrile 2b in the presence of a palladium catalyst such asPd(PPh₃)₄ and a cyanide source such as Zn(CN)₂ in a polar aproticsolvent such as DMF at a temperature of 80° C. based on the chemistrydescribed by Kubota and Rice, Tetrahedron Letters, 1998, 39, 2907-2910.Alternatively, intermediate 2a can be functionalized under Suzukicoupling conditions with an aryl or heteroaryl boronic acid 9, palladiumcatalyst such as PdCl₂(dppf), base such as LiOH, in a mixed solventsystem such as dioxane and water, at elevated temperatures such as 80°C. Under these conditions, the ethyl ester of intermediate 2a can alsobe hydrolyzed to afford compound la directly. Numerous othermetal-mediated functionalizations of intermediates such as 2a will beobvious to those skilled in the art.

While a variety of substituted benzothiophenes 8 are commerciallyavailable, two methods for synthesizing them are depicted in Scheme 4.When the appropriately substituted benzenethiol 10 is readilyaccessible, it may be alkylated with bromoacetaldehyde dimethyl acetalat elevated temperatures in the presence of a base such as potassiumcarbonate in a polar aprotic solvent such as DMF. The resulting acetalintermediate 11 can then undergo cyclocondensation to affordbenzothiophene 8 upon heating in the presence of an acid such aspolyphosphoric acid in a solvent such as chlorobenzene. An alternatepreparation of benzothiophenes proceeds from aryl fluoride 12. Arylfluorides such as 12 may be lithiated at the position adjacent tofluorine by a strong base such as lithium diisopropylamide in a solventsuch as THF at low temperatures such as -70° C. The resultingintermediate can then react with a formyl electrophile such as DMF toafford the 2-fluorobenzaldehyde 13. Nucleophilic aromatic substitutionof the fluorine substituent of 13 with methyl thioglycolate andsubsequent cyclocondensation to benzothiophene 8a can be accomplished ina single vessel by heating the reactants in the presence of a base suchas potassium carbonate in a solvent such as acetonitrile. If desired,the 2-carbomethoxy substituent of benzothiophene 8a may be removed toafford benzothiophene 81). Saponification of the ester as described forthe conversion of 2 to Ia (Scheme 1) yields an acid which may bedecarboxylated using a variety of procedures known to those skilled inthe art. For instance, the acid may be treated with copper powder inquinoline at a temperature of 200° C.

Separation of diastereomers and regioisomers can be carried out atvarious stages in the preparation of compounds I, however, it istypically carried out on compound I using reverse-phase HPLC or on theamide 2 using silica gel chromatography or preparative HPLC with achiral stationary phase.

Analytical HPLC mass spectrometry conditions:

-   LC1: Column: Waters Xterra MS C18 3.5μ, 3.0×50 mm    -   Temperature: 50° C.    -   Eluent: 10:90 to 100:0 v/v acetonitrile/water+0.05% formic acid        over 3.75 min.    -   Flow Rate: 1.2 mL/min, Injection 10 μL    -   Detection: PDA, 200-600 nm    -   MS: mass range 150-750 amu; positive/negative ion electrospray        ionization-   LC2: Column: Waters Xterra IS C-18, 3.5μ, 2.1×20 mm    -   Temperature: 50° C.    -   Eluent: 10:90 to 98:2 v/v acetonitrile/water+0.05% formic acid        over 3.25 min.    -   Flow Rate: 1.5 mL/min, Injection 5 μL    -   Detection: PDA, 200-600 nm    -   MS: mass range 150-750 amu; positive/negative ion electrospray        ionization-   LC3: Column: Waters Xterra IS C-18, 3.5μ, 2.1×20 mm    -   Temperature: 50° C.    -   Eluent: 10:90 to 98:2 v/v acetonitrile/water+0.05% TFA over 3.25        min.    -   Flow Rate: 1.5 mL/min, Injection 5 μL    -   Detection: PDA, 200-600 nm    -   MS: mass range 150-750 amu; positive/negative ion electrospray        ionization-   LC4: Column: Waters Sunfire C18, 5μ, 4.6×50 mm    -   Temperature: 50° C.    -   Eluent: 10:90 to 100:0 v/v acetonitrile/water+0.05% TFA over        3.75 min.    -   Flow Rate: 1.2 mL/min, Injection 10 μL    -   Detection: PDA, 190-300 nm    -   MS: mass range 150-700 amu; positive ion electrospray ionization        Preparative reverse-phase HPLC conditions:    -   Column: Kromasil 100-5-C18, 21.1×100 mm    -   Flow Rate: 20.0 mL/min    -   Fluent: 10:90 to 100:0 v/v acetonitrile/water+0.1% TFA over 10M        min.    -   Temperature: ambient    -   Detection: PDA, 254 nm

Preparative thin layer chromatography (PTLC) was performed on 20×20 cmplates (500 μm thick silica gel). Silica gel chromatography was done ona Biotage Horizon flash chromatography system.

The following examples are provided so that the invention might be morefully understood. They should not be construed as limiting the inventionin any way.

INTERMEDIATE 14-{(1R)-1-[(R)-(4-CHLOROPHENYL)(HYDROXY)METHYL]BUTYL}BENZOIC ACID

Step A. tert-Butyl4-[2-(4-chlorophenyl)-1-propylethan-2-one-1-yl]benzoate

A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF(50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then addedunder nitrogen. After stirring for 15 min,1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followedby tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. Themixture was heated at 60° C. for 8 hours. The mixture was diluted withheptane (100 mL) and poured into a solution of saturated NaHCO₃ (aq) (60mL) and ice (40 g). The resulting layers were separated, and the aqueousphase was back-extracted with methyl tert-butyl ether (50 mL). Thecombined organics were washed with saturated NaHCO₃ (aq) then 10%NaCl(aq). The organic solution was filtered through a bed of silica 60(84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate wasconcentrated to afford an orange oil that was used directly for the nextstep: ¹H NMR (500 MHz, CDCl₃): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (t, J=7.2Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18(m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC1: 1.35 min. (M-tBu+H)⁺317.

Step B. tert-Butyl4-[(1R,2R)-2-(4-chlorophenyl)-1-propylethan-2-hydroxyl-1-yl]benzoate

To degassed 2-propanol (5.0 mL) was addedRuCl₂[(S)-xyl-SEGPHOS][(S)-DAIPEN] (16.2 mg, 0.0134 mmol) and potassiumt-butoxide (300 mg, 2.67 mmol). After this mixture was stirred at roomtemperature for 2 hours, the material obtained in Step A was added in2-propanol (25 mL). This mixture was then treated with hydrogen (100psi) at room temperature for 18 hours. The mixture was concentrated,then the residue was recrystallized from IPAlwater to afford the titlecompound. ‘H NMR (400 MHz, CDCl₃) δ 7.96 (m, 2H), 7.32 (m, 2H), 7.26 (m,2H), 7.22 (m, 2H), 4.76 (dd, J=7.7, 2.9 Hz, 1H), 2.89 (ddd, J=11.5, 7.7,4.2 Hz, 1H), 1.84 (d, J=2.9 Hz, 1H), 1.62 (s, 9H), 1.61 (m, 1H), 1.41(m, 1H), 1.05 (m, 2H), 0.76 (t, J=7.3 Hz, 3H); LC3: 2.38 min.(M−H₂O-tBu+H)⁺301; Chiral SFC Method: Chiralpak AD-H 250×4.6 mm),isocratic 15% MeOH/CO₂, 1.5 mL/min, 200 bar, 35° C., 215 nm, 15 minutes:desired alcohol retention time -9.8 min; enantiomeric alcohol, retentiontime=10.6 min; diastereomeric alcohols retention times=5.2 and 6.3 min.

Step C. 4-{(1R)-1-[(R)-(4-Chlorophenyl)(hydroxy)methyl]butyl}benzoicAcid

Orthophosphoric acid (85 wt %, 11.4 g, 99 mmol) was added to a slurry oftert-butyl4-[(1R,2R)-2-(4-chlorophenyl)-1-propylethan-2-hydroxyl-1-yl]benzoate(7.42 g, 19.8 mmol) in acetonitrile (75 mL). The mixture was purged withnitrogen, then heated at 65° C. for 3.5 hours. The mixture was allowedto cool to 40° C., then water (25 mL) was added dropwise. Oncecrystallization began, additional water (50 mL) was added and themixture was allowed to cool to room temperature. The precipitate wascollected by vacuum filtration, washed with 3:1 water:acetonitrile (35mL), then dried in vacuo at 65° C. overnight to afford the titlecompound as a light green solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.71 (brs, 1H); 7.79 (d, J=8.3 Hz, 2 H); 7.29 (d, J=8.4 Hz, 2H); 7.19-7.25 (m,4H); 5.32 (br s, 1H); 4.76 (d, J=6.3 Hz, 1H); 2.85 (dt, J=10.7, 5.4 Hz,1H); 1.61 (m, 1H); 1.44 (m, 1H); 1.00 (m, 2H); 0.73 (t, J=7.3 Hz, 3H));LC2 3.00 min. (M+H)⁺317.

INTERMEDIATE 2 7-BROMO-5-CHLORO-1-BENZOTHIOPHENE

Step A. 2-Bromo-1-[(2.2-diethoxyethyl)thio]-4-chlorobenzene

Potassium carbonate (0.926 g, 9.34 mmol) then bromoacetaldehyde dimethylacetal (1.35 g, 6.85 mmol) were added to a solution of2-bromo-4-chlorobenzenethiol (1.397 g, 6.23 mmol) in anhydrous DMF (11mL). The mixture was heated at 70° C. for 3 hours. After being allowedto cool to room temperature, the mixture was diluted with ethyl acetateand water. The resulting layers were separated and the aqueous phase wasextracted with ethyl acetate. The combined organics were washed withwater then saturated NaCl (aq), dried over Na₂SO₄, filtered, thenconcentrated. The resulting light yellow oil was used directly for thefollowing step. ¹H NMR (500 MHz, CDCl₃) δ 7.57(d, J=2.0 Hz, 1H); 7.33(d, J=8.5 Hz, 1H); 7.26 (dd, J=8.5, 2.0 Hz, 1H); 4.70 (t, J=5.5 Hz, 1H);3.75-3.68 (m, 2H); 3.61-3.55 (m, 2H); 3.15 (d, J=5.5 Hz, 2H); 1.23 (t,7.0 Hz, 6H).

Step H. 7-Bromo-5-chloro-1-benzothiophene

In a round-bottomed flask fitted with a reflux condenser and additionfunnel, a mixture of chlorobenzene (11 mL) and polyphosphoric acid (7 g)was heated to reflux. A solution of2-bromo-1-[(2,2-diethoxyethypthio]-4-chlorobenzene in chlorobenzene (10mL) was added dropwise via addition funnel then the mixture was refluxedovernight. The viscous mixture was decanted while hot. Additionalchlorobenzene (25 mL) was added to the flask, stirred at 120° C. for 15minutes, then decanted. The remaining viscous mixture in the flask wastreated with toluene (50 mL), water (25 mL), and saturated Na₂CO₃ (aq)(10 mL). The resulting layers were separated, and the aqueous phase wasextracted with toluene. The toluene and chlorobenzene fractions werecombined, washed with saturated Na₂CO₃ (aq), then saturated NaCl (aq),dried over Na₂SO₄, filtered, then concentrated. The residue was purifiedby silica gel chromatography eluting with 0-10% EtOAc/hexanes to affordthe title compound as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.78 (d,J=1.5 Hz, 1H); 7.59 (d, J=5.5 Hz, 1H); 7.53 (d, J=1.5 Hz, 1H); 7.39 (d,J=5.5 Hz, 1H).

INTERMEDIATE 3 7-BROMO-5-(TRIFLUOROMETHYL)-1-BENZOTHIOPHENE

Step A. 3-Bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde

A solution of n-BuLi (2.5 M in hexanes, 1.98 mL, 4.94 mmol) was added toa solution of diisopropylamine (0.700 mL, 4.94 mmol) in THF (10 mL) at-30° C. After 15 minutes, the mixture was cooled to −70° C., then3-bromo-4-fluorobenzotrifluoride (1.00 g, 4.12 mmol) was added. After 30minutes, anhydrous DMF (0.637 mL, 8.23 mmol) was added dropwise. After15 minutes, acetic acid (0.50 mL, 8.2 mmol) was added, then the mixturewas diluted with ethyl acetate and water. The resulting layers wereseparated, and the aqueous phase was extracted with ethyl acetate. Thecombined organics were washed with saturated NaCl (aq), dried overNa₂SO₄, filtered, then concentrated. The resulting light yellow oil wasused directly for the following step. ¹H NMR (500 MHz, CDCl₃) δ 10.38(s, 1H); 8.10-8.15 (m, 2H). LC1: 3.44 min. Compound does not ionize.

Step B. Methyl7-bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylate

Potassium carbonate (1.44 g, 10.42 mmol) then methyl thioglycolate(0.487 g, 4.59 mmol) were added to a degassed solution of3-bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.13 g, 4.17 mmol) inCH₃CN (11 mL). The mixture was stirred at room temperature for 30minutes then refluxed at 100° C. overnight. The mixture was allowed tocool to room temperature, then water (20 mL) was added. The resultinglight yellow solid was collected by vacuum filtration, washed withwater, then dried in vacuo. The resulting ester was used directly forthe following step. ¹H NMR (500 MHz, CDCl₃) δ 8.24 (br s, 1H); 8.15 (brs, 1H); 7.86 (br s,1H); 4.02(br s,3H). LC1: 4.00 min. Compound does notionize.

Step C. 7-Bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylic Acid

A solution of NaOH (4.0 M in water, 5.0 mL, 20 mmol) was added to asolution of methyl7-bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylate (1.00 g, 2.95mmol) in dioxane (11 mL). The mixture was heated at 70° C. overnight,allowed to cool to room temperature, then concentrated. The resultinglight beige solid was partitioned between water (25 mL) and 1:1hexanes:ethyl acetate (15 mL). The resulting layers were separated. Theaqueous layer was adjusted to pH 2 with 2.0 M HCl (aq) then extractedfour times with CH₂Cl₂. The combined CH₂Cl₂ layers were dried overNa₂SO₄, filtered, then concentrated. The resulting acid, a light yellowsolid, was used directly for the following step. LC1: 3.58 min. Compounddoes not ionize.

Step D. 7-Bromo-5-(trifluoromethyl)-1-benzothiophene

To a mixture of quinoline (5 mL) and copper powder (0.39 g, 6.2 mmol) ina sealed tube was added7-bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid (1.0 g,3.1 mmol). The mixture was heated to 200° C. for 20 minutes, thenallowed to cool to room temperature. The mixture was filtered, then thecollected precipitate was washed with toluene. The filtrate wasconcentrated, then the resulting brown oil was diluted with EtOAc andpoured into 6.0 M HCl (aq). The layers were separated, then the aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with 6.0 M HCl (aq), water, then saturated NaCl (aq), dried overNa₂SO4, filtered, then concentrated. The residue was purified by silicagel chromatography eluting with 0-1% EtOAc/hexanes to afford the titlecompound as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 8.10 (br s, 1H);7.77 (br s, 1H); 7.69 (d, J=5.5 Hz, 1H); 7.57 (d, J=5.5 Hz, 1H). LC1:4.02 min. Compound does not ionize.

EXAMPLE 1N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE

Step A. EthylN-(4-{(1S)-1-[(7-bromo-5-chloro-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alaninate

Boron trifluoride diethyl etherate (0.88 mL, 7.0 mmol) was addeddropwise to a solution of INTERMEDIATE 1 (0.400 g, 1.255 mmol) andINTERMEDIATE 2 (0.311 g, 1.255 mmol) in anhydrous dichloromethane (6.5mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes then at roomtemperature overnight. The mixture was diluted with EtOAc then washedwith water. The aqueous phase was extracted with EtOAc. The combinedorganics were washed with saturated NaCl (aq), dried over Na₂SO₄,filtered, then concentrated. The resulting acid, a fluffy brown solid,was used directly for the following step. LC1: 4.34 min. (M−H)⁻545.

To a solution of the product from the previous step in THF (7.3 mL) wasadded N,N′-carbonyldiimidazole (1.017 g, 6.27 mmol). The mixture wasstirred at room temperature for one hour, then f3-alanine ethyl esterhydrochloride (0.964 g, 6.27 mmol) was added, and the mixture wasstirred at 60° C. for 3 hours then at room temperature overnight. Themixture was concentrated, then the residue was purified by silica gelchromatography eluting with 30% EtOAc/hexanes. The resulting materialwas further purified by preparative HPLC (Daicel OD-H column, 2 cm×25cm, 15% IPA/Heptane, 20 mL/min) to provide the title compound as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 7.62 (d, J=8 Hz, 2H); 7.57 (d, J=1.5Hz, 1H); 7.42 (d, J=1.5 Hz, 1H); 7.30-7.35 (m, 5H); 7.27 (d, J=8 Hz,2H); 6.76 (t, J=6 Hz, 1H); 4.47 (d, J=11 Hz, 1H); 4.20 (q, J=7 Hz, 2H);3.71 (q, J=6 Hz, 2H); 3.47 (td, J=11, 3.5 Hz, 1H); 2.64 (t, J=5.5 Hz,2H); 1.31 (t, J=7 Hz, 3H); 1.44-1.56 (m, 2H); 0.99-1.08 (m, 2H); 0.77(t, J=7 Hz, 3H). LC1: 4.34 min. (M+H)⁺646.

Step B. EthylN-(4-{(1S)-1-[(5-chloro-7-cyano-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alaninate

A degassed mixture of ethylN-(4-{(1S)-1-[(7-bromo-5-chloro-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alaninate(0.128 g, 0.198 mmol), zinc cyanide (0.046 g, 0.40 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.114 g, 0.099 mmol) anhydrousDMF (2.9 mL) was heated at 80° C. for 2.5 hours. After cooling to roomtemperature, the solution was concentrated, then the residue waspurified by silica gel chromatography eluting with 35% EtOAc/hexanes.The resulting material was further purified by preparative HPLC (DaicelAD-H chiral column, 2 cm×25 cm, 16% IPA/Heptane, 20 mL/min) to providethe title compound as a white solid. LC1: 4.12 min. (M+H)⁺593.

Step C.N-(4-{(1S)-1-[(5-Chloro-7-cyano-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alanine

A solution of LiOH (2.0 M in water, 4.5 mL, 9.0 mmol) was added to asolution of ethylN-(4-{(1S)-1-[(5-chloro-7-cyano-1-benzothien-3-yl)(4-chlorophenyl)methylibutyl]benzoyl)-β-alaninate(0.100 g, 0.168 mmol) in THF (9.0 mL). The mixture was stirred at roomtemperature for four hours then acidified with acetic acid and extractedwith ethyl acetate. The organics were dried over Na₂SO₄, filtered, thenconcentrated. The resulting residue was purified by reverse-phase HPLCeluting with 20-100% acetonitrile/water containing 0.1% TFA. Followinglyophilization, the material was further purified by silica gelchromatography eluting with 5% MeOH in DCM containing 0.5% acetic acidto afford the title compound as a white solid. ¹H NMR (500 MHz, CDCl₃) δ7.77 (br s, 1H); 7.60 (d, J=5 Hz, 2H); 7.52 (br s, 1H); 7.42 (br s,1H);7.31-7.35 (m, 4H); 7.25 (d, J=7 Hz, 2H); 6.78 (br s,1H); 4.49 (d, J=11Hz, 1H); 3.67 (br s, 2H); 3.44-3.47 (m, 1H); 2.66 (br, 2H); 1.45-1.53(m, 2H); 0.98-1.05 (m, 2H); 0.73 (t, J=7 Hz, 3H). LC1: 3.97 min.(M+H)⁺565.

EXAMPLE 2N-[4-((1S)-1-{(4-CHLOROPHENYL)[5-FLUORO-7-(1-METHYL-1H-PYRAZOL-5-YL)-1-BENZOTHIEN-3-YL]METHYL}PENTYL)BENZOYL]-β-ALANINE

Step A. EthylN-(4-{(1S)-1-[(7-bromo-5-fluoro-1-benzothien-3-yl)(4-chlorophenyl)methyl]pentyl}benzoyl)-β-alaninate

Using the procedures from INTERMEDIATES 1 and 2 and EXAMPLE 1,1-(4-chlorophenyl)hexan-1-one and 2-bromo-4-fluorobenzenethiol wereconverted to the title compound. ¹NMR (500 MHz, CDCl₃): δ 7.62 (d, J=8Hz, 2H); 7.37 (br, 1H); 7.30-7.35 (m, 6H); 7.27 (d, J=8 Hz, 2H); 6.76(t, J=6 Hz, 1H); 4.45 (d, J=11 Hz, 1H); 4.19 (q, J=7 Hz, 2H); 3.71 (q,J=6 Hz, 2H); 3.46 (t, J=10.5 Hz, 1H); 2.64 (t, J=5.5 Hz, 2H); 1.30 (t,J=7 Hz, 3H); 1.47-1.57 (m, 2H); 1.18-1.23 (m, 1H); 1.07-1.14 (m, 1H);0.98-1.03 (m, 2H); 0.75 (t, J=7 Hz, 3H). LC1: 4.23 min. (M+H)⁺644 and646.

Step B.N-[4-((1S)-1-{(4-Chlorophenyl)[5-fluoro-7-(1-methyl-1H-pyrazol-5-yl)-1-benzothien-3-yl]methyl}pentyl)benzoyl]-β-alanine

Dioxane (1.4 mL) and LiOH (2.0 M in water, 0.68 mL, 1.36 mmol) wereadded to a mixture of ethylN-(4-{(1S)-1-[(7-bromo-5-fiuoro-1-benzothien-3-yl)(4-chlorophenyl)methyl]pentyl}benzoyl)-β-alaninate(23.0 mg, 0.036 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester(11.0 mg, 0.053 mmol), and PdCl₂(dppf) (0.029 g, 0.036 mmol) in a sealedmicrowave vial under a nitrogen atmosphere. The mixture was degassedthen irradiated in a microwave reactor at 80° C. for 15 minutes. Themixture was acidified with acetic acid then extracted with ethylacetate. The organic layer was dried over Na₂SO₄, filtered, thenconcentrated. The resulting residue was purified by preparativereverse-phase HPLC eluting with acetonitrile/water+0.1% TFA. Theresulting material was further purified by silica gel chromatographyeluting with 5% MeOH/DCM+0.5% acetic acid to afford the title compound.¹H NMR (500 MHz, CDCl₃): δ 7.57 (br, 3H); 7.29-7.37 (m, 6H); 7.23 (d,J=6 Hz, 2H); 6.94 (d, J=7 Hz, 1H); 6.86 (br, 1H); 6.40 (br, 1H); 4.47(d, J=11 Hz, 1H); 3.71 (br, 3H); 3.62 (br, 2H); 3.43 (t, J=9.5 Hz, 1H);2.59 (br, 2H); 1.45-1.52 (m, 2H); 1.13-1.16 (m, 1H); 1.04-1.06 (m, 1H);0.88-1.00 (m, 2H); 0.68 (t, J=6.5 Hz, 3H). LC1: 3.99 min. (M+H)⁺618.

EXAMPLE 34-{(1S)-1-[(7-BROMO-5-METHYL-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}-N-1H-TETRAZOL-5-YLBENZAMIDE

Step A.4-{(1S)-1-[(7-Bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoicAcid

Using the procedures from INTERMEDIATE 2 and EXAMPLE 1,2-bromo-4-methylbenzenethiol and INTERMEDIATE 1 were converted to thetitle compound. LC2: 2.82 min. Compound does not ionize.

Step B.4-{(1S)-1-[(7-Bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}-N-1H-tetrazol-5-ylbenzamide

A mixture of4-{(1S)-1-[(7-bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoicacid (25.0 mg, 0.047 mmol) and CDI (26 mg, 0.16 mmol) in DMF (1.0 mL)was stirred at RT for 30 minutes in a sealed tube, then5-amino-1H-tetrazole (23.0 mg, 0.260 mmol) was added. The mixture washeated at 100° C. for 12 hours, allowed to cool to RT, then diluted withacetonitrile. The mixture was purified by preparative reverse phase HPLCeluting with 47-100% acetonitrile/water+0.1% TFA. Followinglyophilization, this afforded the title compound as a white solid. ¹HNMR (500 MHz, d₆-DMSO) δ 7.98 (br, 1H); 7.91 (d, J=8 Hz, 2H); 7.84 (br,1H); 7.65 (d, J=8 Hz, 2H); 7.61 (d J=8 Hz, 2H); 7.39 (d, J=8.5 Hz, 2H);7.35 (br,1H); 4.88 (d, J=12 Hz, 1H); 3.79 (t, J=11 Hz, 1H); 2.41 (s,3H); 1.50-1.52 (m, 1H); 1.23-1.30 (m, 1H); 0.92 (q, J=7 Hz, 2H); 0.68(t, J=7 Hz, 3H); LC2: 2.70 min. (M+H)⁺594.

EXAMPLE 44-{(1S)-1-[(7-BROMO-5-METHYL-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}-N-(2H-TETRAZOL-5-YLMETHYL)BENZAMIDE

A mixture of4-{(1S)-1-[(7-bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoicacid (EXAMPLE 3, Step A, 20.0 mg, 0.038 mmol),1-(2H-tetrazol-5-yl)methanamine (10.9 mg, 0.110 mmol), EDC (22.0 mg,0.110 mmol), HOBt (17.0 mg, 0.110 mmol) and DIEA (0.050 mL, 0.29 mmol)in DMF (1 mL) was heated at 65° C. for 12 hours. The mixture was allowedto cool to RT, diluted with acetonitrile, then purified by preparativereverse-phase HPLC eluting with 38-100% acetonitrile/water+0.1% TFA.Following lyophilization, this afforded the title compound as a whitesolid. ¹H NMR (500 MHz, d₆-DMSO) δ 9.04 (br, 1H); 7.96 (s, 1H); 7.84 (s,1H); 7.67 (d, J=8 Hz, 2H); 7.64 (d, J=8 Hz, 2H); 7.52 (d, J=8 Hz, 2H);7.39 (d, J=8.5 Hz, 2H); 7.35 (br, 1H); 4.84 (d, J=11.5 Hz, 1H); 4.67 (d,J=5.5 Hz, 2H); 3.74 (t, J=12 Hz, 1H); 2.40 (s, 3H); 1.44-1.52 (m, 1H);1.24-1.32 (m, 1H); 0.91(q, J=7.5 Hz, 2H); 0.67 (t, J=7 Hz, 3H). LC2:2.63 min. (M+H)⁺608.

Using the chemistry described for the preparation of INTERMEDIATES 1-3and in EXAMPLES 1-4, the compounds in TABLES 1 and 3 were prepared asenantiopure compounds. The data listed are for the most activestereoisomer. Most compounds in TABLE 2 were also prepared as singlestereoisomers, with the data listed being that for the most activestereoisomer. The only exceptions are examples 41 and 42, in which thecompounds are a mixture of the two possible diastereomers at thestereocenter on the substituent labeled “Y” in the general structure.The R¹ and R³ groups that are shown in TABLES 1-3 are specified whenthey represent a value other than a hydrogen atom. The remaining R¹ andR³ groups that are unspecified are hydrogen atoms.

TABLE 1

EXAMPLE R¹ R² R³ LC-MS data  5 4-Cl n-Pr H LC1 3.87 min. (M + H)⁺ 506.5N-(4-{(1S)-1-[1-BENZOTHIEN-3-YL(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE  6 4-Cl n-Pr 5-Cl, 7-Me LC1 4.08 min. (M + H)⁺552 N-(4-{(1S)-1-[(5-CHLORO-7-METHYL-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE  7 4-Cl n-Pr 5-Cl, 7-Br LCl4.26 min. (M + H)⁺ 618.6N-(4-{(1S)-1-[(5-CHLORO-7-BROMO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE  8 4-Cl n-Pr 2-Me LC1 4.02min, (M + H)⁺ 520.6 N-(4-{(1S)-1-[(2-METHYL-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE  9 4-Cl n-Pr 5-F, 7-Cl LC14.13 min. (M + H)⁺ 558N-(4-{(1S)-1-[(5-FLUORO-7-CHLORO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 10 4-OMe n-Pr H LCl 3.62min. (M + H)⁺ 502 N-(4-{(1S)-1-[1-BENZOTHIEN-3-YL(4-METHOXYPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 11 3,4-diCl n-Pr 5-Cl LC2 2.48 min. (M +H)⁺ 576 N-(4-{(1S)-1-[(5-CHLORO-1-BENZOTHIEN-3-YL)(3,4-DICHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 12 3,4-diCl n-Pr 5-Cl,7-Br LC2 2.66 min. (M + H)⁺ 654N-(4-{(1S)-1-[(5-CHLORO-7-BROMO-1-BENZOTHIEN-3-YL)(3,4-DICHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 13 4-Cl n-Pr 5-F, 7-CNLC1 3.95 min, (M + H)⁺ 549N-(4-{(1S)-1-[(5-FLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 14 4-Cl n-Pr 5-Me, 7-CN LC13.99 min. (M + H)⁺ 545N-(4-{(1S)-1-[(5-METHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 15 4-Cl n-Pr 5-CF₃, 7-CNLC1 4.01 min. (M + H)⁺ 599N-(4-{(1S)-1-[(5-TRIFLUOROMETHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 16 4-Cl n-Pr 5,6-diF, 7-CNLC1 3.94 min. (M + H)⁺ 567N-(4-{(1S)-1-[(5,6-DIFLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 17 4-Cl n-Pr 4,5-diF, 7-CNLC1 3.99 min. (M + H)⁺ 567N-(4-{(1S)-1-[(4,5-DIFLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 18 4-Cl n-Pr 2-Me, 5-F,7-CN LC1 3.99 min. (M + H)⁺ 563N-(4-{(1S)-1-[(2-METHYL-5-FLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 19 4-Cl n-Pr 2-Me, 5-Cl,7-CN LC1 4.06 min. (M + H)⁺ 577N-(4-{(1S)-1-[(2-METHYL-5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 20 3,5-diF n-Pr 5-CF₃, 7-CNLC1 3.94 min. (M + H)⁺ 601N-(4-{(1S)-1-[(5-TRIFLUOROMETHYL-7-CYANO-1-BENZOTHIEN-3-YL)(3,5-DIFLUOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 21 3,4-diCl n-Pr 5-Cl,7-CN LC2 2.31 min. (M + H)⁺ 601N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(3,4-DICHLOROPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 22 4-OCF₃ n-Pr 5-F, 7-CNLC1 3.98 min. (M + H)⁺ 599N-(4-{(1S)-1-[(5-FLUOR0-7-CYANO-1-BENZOTHIEN-3-YL)(4-TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 23 4-OCF₃ n-Pr5-Me, 7-CN LC2 2.62 min. (M + H)⁺ 595N-(4-{(1S)-1-[(5-METHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 24 4-OCF₃ n-Pr5-CF₃, 7-CN LC1 4.04 min. (M + H)⁺ 649N-(4-{(1S)-1-[(5-TRIFLUOROMETHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 25 4-OCF₃ n-Pr5-Cl, 7-CN LC2 2.67 min. (M + H)⁺ 615N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 26 4-OCF₃ n-Pr5,6-diF, 7-CN LC2 2.65 min. (M + H)⁺ 617N-(4-{(1S)-1-[(5,6-DIFLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-β-ALANINE 27 4-Cl—CH₂CH₂CF₃ 5-Cl, 7-CN LC1 3.91 min. (M + H)⁺ 619N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]-4,4,4-TRIFLUOROBUTYL}BENZOYL)-β-ALANINE 28 4-Cl—CH₂CH₂CF₃ 5-Me, 7-CN LC2 2.53 min. (M + H)⁺ 599N-(4-{(1S)-1-[(5-METHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]-4,4,4-TRIFLUOROBUTYL}BENZOYL)-β-ALANINE 29 4-Cln-Bu 5-Cl, 7-CN LC1 4.13 min. (M + H)⁺ 579N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]PENTYL}BENZOYL)-β-ALANINE 30 4-Cl n-Bu 5-F, 7-CN LC14.06 min. (M + H)⁺ 561N-(4-{(1S)-1-[(5-FLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]PENTYL}BENZOYL)-β-ALANINE 31 4-Cl n-Bu 5-CF₃, 7-CNLC1 4.20 min. (M + H)⁺ 613N-(4-{(1S)-1-[(5-TRIFLUOROMETHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]PENTYL}BENZOYL)-β-ALANINE 32 4-Cl —CH₂CH(CH₃)₂ 5-Cl,7-CN LC1 4.11 min. (M + H)⁺ 579N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]-4-METHYLBUTYL}BENZOYL)-β-ALANINE 33 4-Cl—CH₂CH(CH₃)₂ 5-F, 7-CN LC1 4.03 min. (M + H)⁺ 563N-(4-{(1S)-1-[(5-FLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]-4-METHYLBUTYL}BENZOYL)-β-ALANINE 34 4-Cl Et 5-Cl,7-CN LC1 3.90 min. (M + H)⁺ 551N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]PROPYL}BENZOYL)-β-ALANINE 35 4-Cl n-Pr

LC1 3.93 min. (M + H)⁺ 620N-[4-((1S)-1-{(4-CHLOROPHENYL)[5-CHLORO-7-(1-METHYL-1H-PYRAZOL-4-YL)-1-BENZOTHIEN-3-YL]METHYL}BUTYL)BENZOYL]-β-ALANINE 36 4-OCF₃ n-Pr

LC1 3.86 min. (M + H)⁺ 640N-[4-((1S)-1-{(4-TRIFLUOROMETHOXYPHENYL)[5-FLUORO-7-(1H-PYRAZOL-3-YL)-1-BENZOTHIEN-3-YL]METHYL}BUTYL)BENZOYL]-β-ALANINE 37 4-Cl n-Bu

LC1 3.93 min. (M + H)⁺ 604N-[4-((1S)-1-{(4-CHLOROPHENYL)[5-FLUORO-7-(1H-PYRAZOL-3-YL)-1-BENZOTHIEN-3-YL]METHYL}PENTYL)BENZOYL]-β-ALANINE 38 4-Cl n-Pr

LC2 2.56 min. (M + H)⁺ 607N-[4-((1S)-1-{(4-CHLOROPHENYL)[5-CHLORO-7-(1H-ISOXAZOL-4-YL)-1-BENZOTHIEN-3-YL]METHYL}BUTYL)BENZOYL]-β-ALANINE

TABLE 2

EXAMPLE Y LC-MS data 39

LC3 2.59 min. (M + H)⁺ 614(2S)-3-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]-2- HYDROXYPROPANOIC ACID40

LC3 2.63 min. (M + H)⁺ 6343-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]-2,2- DIFLUOROPROPANOIC ACID 41

LC3 2.70 min. (M + H)⁺ 6123-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]-2- METHYLPROPANOIC ACID 42

LC3 2.69 min. (M + H)⁺ 6123-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]-3- METHYLPROPANOIC ACID 43

LC3 2.36 min. (M + H)⁺ 6342-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]ETHANE SULFONIC ACID 44

LC3 2.57 min. (M + H)⁺ 5973-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]PROPANOIC AMIDE

TABLE 3

EXAMPLE R¹ R² R³ LC-MS data 45 4-Cl n-Pr H LC1 4.07 min. (M + H)⁺ 520.6N-[4-((1S)-1-{(4-CHLOROPHENYL)[3-METHYL-1-BENZOTHIEN-2-YL]METHYL}BUTYL)BENZOYL]- β-ALANINE 46 4-Cl n-Pr 5-Cl LC14.19 min. (M + H)⁺ 554.6 N-[4-((1S)-1-{(4-CHLOROPHENYL)[3-METHYL-5-CHLORO-1-BENZOTHIEN-2-YL]METHYL}BUTYL) BENZOYL]-β-ALANINE 47 4-Cl n-Pr7-Cl LC1 4.22 min. (M + H)⁺ 554.5N-[4((1S)-1-{(4-CHLOROPHENYL)[3-METHYL-7-CHLORO-1-BENZOTHIEN-2-YL]METHYL}BUTYL) BENZOYL]-β-ALANINE 48 4-OMe n-Pr5-Cl LC1 3.91 min. (M + H)⁺ 550.6N-[4((1S)-1-{(4-METHOXYPHENYL)[3-METHYL-5-CHLORO-1-BENZOTHIEN-2-YL]METHYL}BUTYL) BENZOYL]-β-ALANINE

Biological Assays

The ability of the compounds of the present invention to inhibit thebinding of glucagon and their utility in treating or preventing type 2diabetes mellitus and the related conditions can be demonstrated by thefollowing in vitro assays.

Glucagon Receptor Binding Assay

A stable CHO (Chinese hamster ovary) cell line expressing cloned humanglucagon receptor was maintained as described (Chicchi, et. al. J BiolChem 272, 7765-9(1997); Cascieri, et. al. J Biol Chem 274,8694-7(1999)). To deteiinine antagonistic binding affinity of compounds,0.001-0.003 mg of cell membranes from these cells were pre-incubatedwith 0.100 mg WGA-coated PVT SPA beads (Amersham) for 20 minutes at roomtemperature in 25 μL of a buffer containing 50 mM Tris-HCl (pH 7.5), 5mM MgCl₂, 2 mM EDTA, 0.1% BSA and 3% glycerol in Costar 384 well plateswith clear bottoms (#3706). Next, 25 μL of ¹²⁵1-Glucagon (New EnglandNuclear, Mass.) (1×10⁴⁴ mol per well) and either 1 μL solutions of testcompounds or 0.001 mM unlabeled glucagon or DMSO were added and mixed.After 4-12 hours incubation at room temperature, the radioactivity boundto the cell membranes was determined in a radioactive emission detectioncounter (Wallac-Microbeta). Data were analyzed using the Data Analyzersoftware program of Merck & Co., Inc. The IC₅₀ values were calculatedusing non-linear regression analysis assuming single-site competition.IC₅₀ values for the compounds of the invention are generally in therange of as low as about 1 nM to as high as about 500 nM, and thus haveutility as glucagon antagonists. The IC₅₀ values are shown below inTABLE 4 for the more active isomer of indicated compounds.

TABLE 4 Example IC₅₀ (nM) 1 6.2 2 4.7 3 2.3 4 2.5 6 28 8 2.2 13 1.1 141.3 15 1.7 19 7.8 21 0.7 23 0.2 25 0.1 27 0.2 29 0.4 32 1.0 40 11.8 433.4 45 1.8Inhibition of Glucagon-Stimulated Intracellular cAMP Formation

Exponentially growing CHO cells expressing human glucagon receptor wereharvested with the aid of enzyme-free dissociation media (SpecialtyMedia), pelleted at low speed, and re-suspended in the Cell StimulationBuffer included in the Flash Plate cAMP kit (New England Nuclear,SMP0004A). The adenylate cyclase assay was conducted as per manufacturerinstructions. Briefly, compounds were diluted from stocks in DMSO andadded to cells at a final DMSO concentration of 5%. Cells prepared asabove were preincubated in flash plates coated with anti-cAMP antibodies(NEN) in the presence of compounds or DMSO controls for 30 minutes, thenstimulated with glucagon (250 pM) for an additional 30 minutes. The cellstimulation was stopped by addition of equal amounts of a detectionbuffer containing lysis buffer as well as ¹²⁵I-labeled cAMP tracer(NEN). After 3 hours of incubation at room temperature the boundradioactivity was determined in a liquid scintillation counter(TopCount-Packard Instruments). Basal activity (100% inhibition) wasdetermined using the DMSO control while 0% inhibition was defined at theamount of pmol cAMP produced by 250 pM glucagon. The resulting amount ofcAMP generated per compound dose was back-calculated from a cAMPstandard curve based on the percent inhibition achieved at each dose.The calculated cAMP levels were plotted versus compound dose to obtainIC₅₀ values using non-linear four-parameter curve fitting with AssayData Analyzer software (Merck & Co., Inc.).

Certain embodiments of the invention have been described in detail;however, numerous other embodiments are contemplated as falling withinthe invention. Thus, the claims are not limited to the specificembodiments described herein. All patents, patent applications andpublications that are cited herein are hereby incorporated by referencein their entirety.

1. A compound represented by formula I:

or a pharmaceutically acceptable salt thereof wherein: each R¹represents H or is selected from the group consisting of halo, CN, OH,NO₂, CO₂R^(a), NR^(a)R^(b), S(O)_(p)R^(a), C₁₋₁₀alkyl, C₂₋₁₀alkenyl orC₁₋₁₀alkoxy, the alkyl amd alkenyl portions of C₁₋₁₀alkyl, C₂₋₁₀alkenyland C₁₋₁₀alkoxy being optionally substituted with 1-5 halo atoms up toperhalo; and further optionally substituted with 1 group selected fromOH, oxo and C₁₋₆alkoxy; p represents 0, 1 or 2; each R^(a) and R^(b)independently represents H or C₁₋₄alkyl optionally substituted with 1-5halo atoms up to perhalo; and further optionally substituted with 1group selected from OH, oxo and C₁₋₆alkoxy; R² represents C₁₋₆alkyl orC₂₋₆alkenyl, each optionally substituted with 1-5 halo atoms up toperhalo, and further optionally substituted with 1 group selected fromOH, oxo and C₁₋₆alkoxy; each R³ represents H or is selected from thegroup consisting of halo; CN; OH; NO₂; CO₂R^(a); NR^(a)R^(b);S(O)_(p)R^(a); a 5-membered heteroaryl ring containing 1-3 nitrogenatoms, 0-1 oxygen or sulfur atom, and optionally substituted with 1-2C₁₋₄alkyl groups; C₁₋₁₀alkyl; C₂₋₁₀alkenyl and C₁₋₁₀alkoxy, the alkyland alkenyl portions of C₁₋₁₀alkyl, C₂₋₁₀alkenyl and C₁₋₁₀alkoxy beingoptionally substituted with 1-5 halo atoms up to perhalo; and furtheroptionally substituted with 1 group selected from OH, oxo, NR^(a)R^(b)and C₁₋₆alkoxy; each R⁴ independently represents H or is selected fromthe group consisting of halo, OH, C₁₋₄alkyl, OC₁₋₄alkyl, haloC₁₋₄alkyland haloOC₁₋₄alkyl; m represents 0, 1 or 2; such that when m represents0 or 1, Z represents tetrazolyl; and when m represents 2, Z represents amember selected from the group consisting of CO₂H, SO₃H and C(O)NH₂. 2.A compound in accordance with claim 1 or a pharmaceutically acceptablesalt thereof wherein each R¹ represents H or is selected from the groupconsisting of halo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkyl andhaloC₁₋₆ alkoxy.
 3. A compound in accordance with claim 1 or apharmaceutically acceptable salt thereof wherein each R¹ represents H oris selected from the group consisting of: halo selected from fluoro andchloro; CN; CH₃; OCH₃; CF₃ and OCF₃.
 4. A compound in accordance withclaim 1 or a pharmaceutically acceptable salt thereof wherein R²represents a member selected from the group consisting of: C₁₋₆alkyl andC₃₋₄alkenyl, each optionally substituted with 1-3 halo atoms.
 5. Acompound in accordance with claim 1 or a pharmaceutically acceptablesalt thereof wherein R² represents C₂₋₅alkyl optionally substituted with1-3 halo atoms.
 6. A compound in accordance with claim 1 or apharmaceutically acceptable salt thereof wherein R² is selected from thegroup consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and 3-methylbutyl, each optionally substituted with 1-3 haloatoms selected from fluoro and chloro.
 7. A compound in accordance withclaim 1 or a pharmaceutically acceptable salt thereof wherein R² isselected from the group consisting of ethyl, n-propyl, n-butyl,CH₂CH(CH₃)₂, CH₂CH₂CH(CH₃)₂ and CH₂CH₂CF₃.
 8. A compound in accordancewith claim 1 or a pharmaceutically acceptable salt thereof wherein eachR³ represents H or is selected from the group consisting of halo, CN,OH, SCH₃ , SO₂CH₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkyl,haloC₁₋₆alkoxy and a 5-membered heteroaryl ring containing 1-2 nitrogenatoms and 0-1 oxygen atom, said ring being optionally substituted with1-2 C₁₋₄alkyl groups.
 9. A compound in accordance with claim 1 or apharmaceutically acceptable salt thereof wherein each R³ represents H oris selected from the group consisting of halo which is selected from F,Cl and Br, CN, OH, SCH₃, SO₂CH₃, C₁₋₂alkyl, C₁₋₂alkoxy, haloC₁₋₂alkyland haloC₁₋₂alkoxy wherein the halo portion of haloC₁₋₂alkyl andhaloC₁₋₂alkoxy is selected from F and Cl, and a 5-membered heteroarylring containing 1-2 nitrogen atoms and 0-1 oxygen atom, said ring beingoptionally substituted with 1-2 C₁₋₄alkyl groups.
 10. A compound inaccordance with claim 1 or a pharmaceutically acceptable salt thereofwherein each R³ represents H, F, Cl, Br, CN, OH, CH₃, OCH₃, OCH₂CH₃,CHF₂, CF₃, SCH₃, SO₂CH₃, OCHF₂, OCF₃ and a 5-membered heteroaryl ringcontaining 1-2 nitrogen atoms, 0-1 oxygen atom and being optionallysubstituted with 1 C₁₋₂alkyl group.
 11. A compound in accordance withclaim 1 or a pharmaceutically acceptable salt thereof wherein each R⁴represents H, halo selected from F and Cl, OH, C₁₋₂alkyl, C₁₋₂alkoxy,haloC₁₋₂alkyl and haloC₁₋₂alkoxy wherein the halo portion ofhaloC₁₋₂alkyl and haloC₁₋₂alkoxy is selected from F and Cl.
 12. Acompound in accordance with claim 1 or a pharmaceutically acceptablesalt thereof wherein each R⁴ represents H, F, Cl, OH, CH₃, OCH₃, CF₃,and OCF₃.
 13. A compound in accordance with claim 1 or apharmaceutically acceptable salt thereof wherein each R⁴ represents H,F, CH₃ or OH.
 14. A compound in accordance with claim 1 or apharmaceutically acceptable salt thereof wherein m represents 0 or 1 andZ represents tetrazolyl.
 15. A compound in accordance with claim 1 or apharmaceutically acceptable salt thereof wherein m is 2 and Z representsCO₂H.
 16. A compound in accordance with claim 1 or a pharmaceuticallyacceptable salt thereof wherein: each R¹ represents H or is selectedfrom the group consisting of halo, CN, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkyl and haloC₁₋₆alkoxy; R² represents a member selected fromthe group consisting of: C₁₋₆alkyl and C₃₋₄alkenyl, each optionallysubstituted with 1-3 halo atoms; each R³ represents H or is selectedfrom the group consisting of halo, CN, OH, SCH₃, SO₂CH₃, C₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy and a 5-membered heteroarylring containing 1-2 nitrogen atoms and 0-1 oxygen atom, said ring beingoptionally substituted with 1-2 C₁₋₄alkyl groups; each R⁴ represents H,halo selected from F and Cl, OH, C₁₋₂alkyl, C₁₋₂alkoxy, haloC₁₋₂alkyland haloC₁₋₂alkoxy wherein the halo portion of haloC₁₋₂alkyl andhaloC₁₋₂alkoxy is selected from F and Cl; and m is 0 or 1 and Z istetrazolyl, or m is 2 and Z represents CO₂H.
 17. A compound inaccordance with claim 1 selected from the group consisting of:

TABLE 1

EXAMPLE R¹ R² R³  5 4-Cl n-Pr H  6 4-Cl n-Pr 5-Cl, 7-Me  7 4-Cl n-Pr5-Cl, 7-Br  8 4-Cl n-Pr 2-Me  9 4-Cl n-Pr 5-F, 7-Cl 10 4-OMe n-Pr H 113,4-diCl n-Pr 5-Cl 12 3,4-diCl n-Pr 5-Cl, 7-Br 13 4-Cl n-Pr 5-F, 7-CN 144-Cl n-Pr 5-Me, 7-CN 15 4-Cl n-Pr 5-CF₃, 7-CN 16 4-Cl n-Pr 5,6-diF, 7-CN17 4-Cl n-Pr 4,5-diF, 7-CN 18 4-Cl n-Pr 2-Me, 5-F, 7-CN 19 4-Cl n-Pr2-Me, 5-Cl, 7-CN 20 3,5-diF n-Pr 5-CF₃, 7-CN 21 3,4-diCl n-Pr 5-Cl, 7-CN22 4-OCF₃ n-Pr 5-F, 7-CN 23 4-OCF₃ n-Pr 5-Me, 7-CN 24 4-OCF₃ n-Pr 5-CF₃,7-CN 25 4-OCF₃ n-Pr 5-Cl, 7-CN 26 4-OCF₃ n-Pr 5,6-diF, 7-CN 27 4-Cl—CH₂CH₂CF₃ 5-Cl, 7-CN 28 4-Cl —CH₂CH₂CF₃ 5-Me, 7-CN 29 4-Cl n-Bu 5-Cl,7-CN 30 4-Cl n-Bu 5-F, 7-CN 31 4-Cl n-Bu 5-CF₃, 7-CN 32 4-Cl—CH₂CH(CH₃)₂ 5-Cl, 7-CN 33 4-Cl —CH₂CH(CH₃)₂ 5-F, 7-CN 34 4-Cl Et 5-Cl,7-CN 35 4-Cl n-Pr

36 4-OCF₃ n-Pr

37 4-Cl n-Bu

38 4-Cl n-Pr

TABLE 2

EXAMPLE Y   39

40

41

42

43

44

TABLE 3

EXAMPLE R¹ R² R³ 45 4-Cl n-Pr H 46 4-Cl n-Pr 5-Cl 47 4-Cl n-Pr 7-Cl 484-OMe n-Pr 5-Cl

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound in accordance with claim 1 or apharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier.
 19. A pharmaceutical composition inaccordance with claim 18 further comprised of a member selected from thegroup consisting of: simvastatin, mevastatin, ezetimibe, atorvastatin,metformin, sibutramine, orlistat, Qnexa, topiramate, naltrexone,bupriopion, phentermine, losartan, hydrochlorothiazide, buformin,phenformin, troglitazone, pioglitazone, rosiglitazone, insulin,somatostatin, voglibose, miglitol, acarbose, sitagliptin, vildagliptin,saxagliptin, alogliptin, acetohexamide, carbutamide, chlorpropamide,glibornuride, gliclazide, glimerpiride, glipizide, gliquidine,glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide,tolazamide, tolbutamide, tolcyclamide, nateglinide, repaglinide,rimonabant and taranabant.
 20. A method of treating type 2 diabetesmellitus in a mammalian patient in need of such treatment comprisingadministering to said patient a compound in accordance with claim 1 or apharmaceutically acceptable salt thereof in an amount that is effectiveto treat said type 2 diabetes mellitus. 21-29. (canceled)